Details of the Researcher

PHOTO

Yoko Aoki
Section
Graduate School of Medicine
Job title
Professor
Degree

  • 博士（医学）（東北大学）

Profile

臨床遺伝専門医・指導医、
小児科専門医

東北大学医学部卒業。岩手県立中央病院小児科、東北大学大学院医学系研究科博士課程修了。ハーバード大学医学部・マサチューセッツ総合病院脳神経センターにて神経幹細胞におけるSHP2（のちにヌーナン症候群の原因として報告されるPTPN11）の役割についての基礎研究を行った。2000年日本学術振興会特別研究員（PD)、2000年10月東北大学大学院医学系研究科遺伝医療学分野助教、2008年に同准教授。2015年より遺伝医療学分野教授、東北大学病院遺伝科科長・遺伝子診療部部長となる。ヌーナン症候群類縁疾患において、HRAS, BRAF, KRAS, RIT1などの生殖細胞系列での変異が原因であることを世界に先駆けて報告し、RAS/MAPK症候群（現在はRASopathies)という新しい疾患概念を確立しました。「遺伝性疾患の病態解明から新しい生命現象を明らかにする」ことを目標に、さまざまな希少性疾患の原因解明やモデル生物による病態解明研究を行っています。

GermlineにRASの遺伝子変異を持つRASopathiesモデルマウス3疾患4遺伝子（HRAS, BRAF, RIT1, LZTR1）を作製しました。共同研究募集中です。https://mus.brc.riken.jp/ja/mouse_of_month/nov_2022_mm

 

Committee Memberships 12

  • 日本学術振興会 学術システム研究センター 主任研究員

    2022/07 - Present

  • 日本人類遺伝学会　理事

    2020/11 - Present

  • 日本小児科学会　学術委員会 委員

    2020 - Present

  • 日本小児遺伝学会　評議員

    2018 - Present

  • 日本遺伝カウンセリング学会　評議員

    2017 - Present

  • 日本遺伝子診療学会　理事

    2017 - Present

  • 日本人類遺伝学会　評議員

    2009/04 - Present

  • 日本遺伝子診療学会　副理事長

    2021/04 - 2025/03

  • 日本小児科学会　国際渉外委員

    2017 - 2022

  • 日本人類遺伝学会　キャリアパス委員会 委員長

    2016 - 2019

  • 日本人類遺伝学会 男女共同参画委員　委員

    2008/04 - 2019

  • 日本学術会議　連携会員

    2020/10 -

Show all ︎Show first 5

Professional Memberships 6

  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

  • THE JAPANESE SOCIETY FOR GENETIC COUNSELING

  • 日本小児遺伝学会

  • 日本遺伝子診療学会

  • JAPAN PEDIATRIC SOCIETY

  • THE JAPAN SOCIETY OF HUMAN GENETICS

︎Show all ︎Show first 5

Research Interests 12

  • ゲノム解析

  • RASシグナル伝達

  • 心臓の発生

  • ヒストン修飾

  • がん原遺伝子

  • 細胞老化

  • 遺伝性腫瘍

  • 血管腫・血管奇形

  • RASの分解機構

  • 血小板減少

  • リンパ管の発生と疾患

  • 疾患モデル生物

Research Areas 2

  • Life sciences / Fetal medicine/Pediatrics /

  • Life sciences / Medical biochemistry /

Awards 3

  1. 東北大学医学部奨学賞金賞

    2007/01　東北大学医学部

  2. 日本人類遺伝学会奨励賞

    2006/10　日本人類遺伝学会

  3. 日本遺伝子診療学会学術奨励賞

    2006/07　日本遺伝子診療学会

Papers 203

  1. Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice

    Taiki Abe, Kaho Morisaki, Tetsuya Niihori, Miho Terao, Shuji Takada, Yoko Aoki

    JCI Insight　2024/10/01

    Publisher: American Society for Clinical Investigation

    DOI： 10.1172/jci.insight.182382 　

    eISSN： 2379-3708

  2. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease. International-journal Peer-reviewed

    Akifumi Nozawa, Michio Ozeki, Tetsuya Niihori, Natsuko Suzui, Tatsuhiko Miyazaki, Yoko Aoki

    Journal of human genetics　65　(11)　995-1001　2020/06/26

    DOI： 10.1038/s10038-020-0794-y 　

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    Gorham-Stout disease (GSD), a rare disorder of unknown etiology, is characterized by massive osteolysis that is associated with proliferation and dilation of lymphatic vessels. Variants in cancer-associated genes have been described in complex lymphatic anomalies. To explore the pathogenesis of GSD, we performed the amplicon-based deep sequencing on 50 cancer-related genes to assay affected tissues from the six patients with GSD. In one patient, a somatic activating KRAS c.182A > G variant (p.Q61R) was detected in 1% of the tissue sample. Conversely, the mutant allele was not detected in uninvolved normal skin and blood samples. Histopathology of the patient's tissue sample showed proliferation of abnormal lymphatic and blood vascular endothelial cells, osteoclasts, and activated macrophages. The activating KRAS variant is a known 'hotspot' variant, frequently identified in several types of human cancer. This is the first report of identifying a pathogenic variant in a patient with GSD. This finding may set the stage for elucidation of pathophysiology and the development of novel therapies for GSD.

  3. Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis. International-journal Peer-reviewed

    Michio Ozeki, Yoko Aoki, Akifumi Nozawa, Shiho Yasue, Saori Endo, Yumiko Hori, Kentaro Matsuoka, Tetsuya Niihori, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Toshiyuki Fukao

    Orphanet journal of rare diseases　14　(1)　215-215　2019/09/11

    DOI： 10.1186/s13023-019-1191-5 　

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    BACKGROUND: Kaposiform lymphangiomatosis (KLA) has recently been distinguished as a novel subtype of generalized lymphatic anomaly (GLA) with foci of spindle endothelial cells. All cases of KLA involve multiple organs and have an unfavorable prognosis. However, the molecular pathogenesis is unknown, and there are no useful biomarkers. In the present study, we performed genetic analysis to elucidate the cause of this disease and detect biomarkers for it. METHODS: We performed whole-exome sequencing of DNA samples from leukocytes and a biopsy specimen and analyzed cell-free DNA (cfDNA) from plasma and pleural effusion of patients to identify the NRAS c.182A > G (p.Q61R) mutation using the droplet digital polymerase chain reaction (ddPCR). RESULTS: All KLA patients (patients 1-5) had invasive and aggressive features (hemorrhagic pleural effusions, coagulation disorder, and thrombocytopenia) and characteristic findings of KLA in their pathological examinations. In whole exome sequencing for patient 1, c.182A > G missense variant (p.Q61R) in NRAS was identified in fresh frozen samples of a mass on the left chest wall at a frequency of 5% of total alleles but not in his blood leukocytes. Furthermore, the same mutation was detected in cfDNA isolated from plasma and pleural effusion by using ddPCR. ddPCR analysis of plasma/pleural effusion samples from an additional four KLA patients showed that the same mutation was detected in isolated cfDNA in three of the four, as well as in a tissue sample from one of the three plasma/effusion-positive patients that had been obtained to confirm the mutation. CONCLUSION: These results provide the first evidence that NRAS oncogenic variant was identified in DNA samples from KLA patients from not only two affected lesions but also plasma and pleural effusion.

  4. New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis. International-journal Peer-reviewed

    Shingo Takahara, Shin-Ichi Inoue, Sachiko Miyagawa-Tomita, Katsuhisa Matsuura, Yasumi Nakashima, Tetsuya Niihori, Yoichi Matsubara, Yoshikatsu Saiki, Yoko Aoki

    EBioMedicine　42　43-53　2019/04

    DOI： 10.1016/j.ebiom.2019.03.014 　

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    BACKGROUND: Noonan syndrome (NS) is a genetic disorder characterized by short stature, a distinctive facial appearance, and heart defects. We recently discovered a novel NS gene, RIT1, which is a member of the RAS subfamily of small GTPases. NS patients with RIT1 mutations have a high incidence of hypertrophic cardiomyopathy and edematous phenotype, but the specific role of RIT1 remains unclear. METHODS: To investigate how germline RIT1 mutations cause NS, we generated knock-in mice that carried a NS-associated Rit1 A57G mutation (Rit1A57G/+). We investigated the phenotypes of Rit1A57G/+ mice in fetal and adult stages as well as the effects of isoproterenol on cardiac function in Rit1A57G/+ mice. FINDINGS: Rit1A57G/+ embryos exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation. Surviving Rit1A57G/+ mice had a short stature, craniofacial abnormalities and splenomegaly. Cardiac hypertrophy and cardiac fibrosis with increased expression of S100A4, vimentin and periostin were observed in Rit1A57G/+ mice compared to Rit1+/+ mice. Upon isoproterenol stimulation, cardiac fibrosis was drastically increased in Rit1A57G/+ mice. Phosphorylated (at Thr308) AKT levels were also elevated in isoproterenol-treated Rit1A57G/+ hearts. INTERPRETATION: The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS-associated features. Biochemical analysis indicates that the AKT signaling pathway might be related to downstream signaling in the RIT1 A57G mutant at a developmental stage and under β-adrenergic stimulation in the heart. FUND: The Grants-in-Aid were provided by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science KAKENHI Grant.

  5. Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis. International-journal Peer-reviewed

    Daiju Oba, Shin-Ichi Inoue, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Tetsuya Niihori, Seiji Yamaguchi, Yoichi Matsubara, Yoko Aoki

    EBioMedicine　27　138-150　2018/01

    DOI： 10.1016/j.ebiom.2017.11.029 　

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    Costello syndrome is a "RASopathy" that is characterized by growth retardation, dysmorphic facial appearance, hypertrophic cardiomyopathy and tumor predisposition. >80% of patients with Costello syndrome harbor a heterozygous germline G12S mutation in HRAS. Altered metabolic regulation has been suspected because patients with Costello syndrome exhibit hypoketotic hypoglycemia and increased resting energy expenditure, and their growth is severely retarded. To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (HrasG12S/+ mice) as a mouse model of Costello syndrome. On a high-fat diet, HrasG12S/+ mice developed a lean phenotype with microvesicular hepatic steatosis, resulting in early death compared with wild-type mice. Under starvation conditions, hypoketosis and elevated blood levels of long-chain fatty acylcarnitines were observed, suggesting impaired mitochondrial fatty acid oxidation. Our findings suggest that the oncogenic Hras mutation modulates energy homeostasis in vivo.

  6. Recent advances in RASopathies. International-journal Peer-reviewed

    Yoko Aoki, Tetsuya Niihori, Shin-ichi Inoue, Yoichi Matsubara

    Journal of human genetics　61　(1)　33-9　2016/01

    DOI： 10.1038/jhg.2015.114 　

    ISSN： 1434-5161

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    RASopathies or RAS/mitogen-activated protein kinase (MAPK) syndromes are a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS/MAPK signaling pathway. These disorders include neurofibromatosis type I, Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome), Costello syndrome, cardiofaciocutaneous (CFC) syndrome, Noonan-like syndrome, hereditary gingival fibromatosis and capillary malformation-arteriovenous malformation. Recently, novel gene variants, including RIT1, RRAS, RASA2, A2ML1, SOS2 and LZTR1, have been shown to be associated with RASopathies, further expanding the disease entity. Although further analysis will be needed, these findings will help to better elucidate an understanding of the pathogenesis of these disorders and will aid in the development of potential therapeutic approaches. In this review, we summarize the novel genes that have been reported to be associated with RASopathies and highlight the cardiovascular abnormalities that may arise in affected individuals.

  7. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. International-journal Peer-reviewed

    Yoko Aoki, Tetsuya Niihori, Toshihiro Banjo, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Tsutomu Ogata, Fumio Takada, Michihiro Yano, Toru Ando, Tadataka Hoshika, Christopher Barnett, Hirofumi Ohashi, Hiroshi Kawame, Tomonobu Hasegawa, Takahiro Okutani, Tatsuo Nagashima, Satoshi Hasegawa, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Shin-Ichi Inoue, Yusuke Watanabe, Toshihiko Ogura, Yoichi Matsubara

    American journal of human genetics　93　(1)　173-80　2013/07/11

    DOI： 10.1016/j.ajhg.2013.05.021 　

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    RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

  8. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. International-journal Peer-reviewed

    Fumiaki Kamada, Yoko Aoki, Ayumi Narisawa, Yu Abe, Shoko Komatsuzaki, Atsuo Kikuchi, Junko Kanno, Tetsuya Niihori, Masao Ono, Naoto Ishii, Yuji Owada, Miki Fujimura, Yoichi Mashimo, Yoichi Suzuki, Akira Hata, Shigeru Tsuchiya, Teiji Tominaga, Yoichi Matsubara, Shigeo Kure

    Journal of human genetics　56　(1)　34-40　2011/01

    DOI： 10.1038/jhg.2010.132 　

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    Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = 71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

  9. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. International-journal Peer-reviewed

    Tetsuya Niihori, Yoko Aoki, Yoko Narumi, Giovanni Neri, Hélène Cavé, Alain Verloes, Nobuhiko Okamoto, Raoul C M Hennekam, Gabriele Gillessen-Kaesbach, Dagmar Wieczorek, Maria Ines Kavamura, Kenji Kurosawa, Hirofumi Ohashi, Louise Wilson, Delphine Heron, Dominique Bonneau, Giuseppina Corona, Tadashi Kaname, Kenji Naritomi, Clarisse Baumann, Naomichi Matsumoto, Kumi Kato, Shigeo Kure, Yoichi Matsubara

    Nature genetics　38　(3)　294-6　2006/03

    DOI： 10.1038/ng1749 　

    ISSN： 1061-4036

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    Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.

  10. Germline mutations in HRAS proto-oncogene cause Costello syndrome. International-journal Peer-reviewed

    Yoko Aoki, Tetsuya Niihori, Hiroshi Kawame, Kenji Kurosawa, Hirofumi Ohashi, Yukichi Tanaka, Mirella Filocamo, Kumi Kato, Yoichi Suzuki, Shigeo Kure, Yoichi Matsubara

    Nature genetics　37　(10)　1038-40　2005/10

    DOI： 10.1038/ng1641 　

    ISSN： 1061-4036

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    Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors. We identified four heterozygous de novo mutations of HRAS in 12 of 13 affected individuals, all of which were previously reported as somatic and oncogenic mutations in various tumors. Our observations suggest that germline mutations in HRAS perturb human development and increase susceptibility to tumors.

  11. Overexpression of p27(Kip1) lengthens the G(1) phase in a mouse model that targets inducible gene expression to central nervous system progenitor cells Peer-reviewed

    T Mitsuhashi, Y Aoki, YZ Eksioglu, T Takahashi, PG Bhide, SA Reeves, VS Caviness

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　98　(11)　6435-6440　2001/05

    DOI： 10.1073/pnas.111051398 　

    ISSN： 0027-8424

  12. ISOLATION AND CHARACTERIZATION OF MUTATIONS IN THE HUMAN HOLOCARBOXYLASE SYNTHETASE CDNA Peer-reviewed

    Y SUZUKI, Y AOKI, Y ISHIDA, Y CHIBA, A IWAMATSU, T KISHINO, N NIIKAWA, Y MATSUBARA, K NARISAWA

    NATURE GENETICS　8　(2)　122-128　1994/10

    DOI： 10.1038/ng1094-122 　

    ISSN： 1061-4036

  13. Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan. International-journal

    Kinuko Ohneda, Yoichi Suzuki, Yohei Hamanaka, Shu Tadaka, Muneaki Shimada, Junko Hasegawa-Minato, Masanobu Takahashi, Nobuo Fuse, Fuji Nagami, Hiroshi Kawame, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Tomohiro Nakamura, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Shin-Ichi Kuriyama, Yoko Izumi, Ritsuko Shimizu, Mikako Tochigi, Tokiwa Motonari, Hideki Tokunaga, Atsuo Kikuchi, Atsushi Masamune, Yoko Aoki, Chikashi Ishioka, Takanori Ishida, Masayuki Yamamoto

    Journal of human genetics　70　(3)　147-157　2025/03

    DOI： 10.1038/s10038-024-01314-w 　

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    Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants' understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.

  14. Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations

    Akira Moriya, Shin-ichi Inoue, Fumihito Saitow, Moe Keitoku, Noato Suzuki, Etsumi Oike, Eriko Urano, Eiko Matsumoto, Hidenori Suzuki, Yoko Aoki, Hiroshi Ohnishi

    Human Molecular Genetics　2025/01/08

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/hmg/ddae196 　

    ISSN： 0964-6906

    eISSN： 1460-2083

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    Abstract Constitutively active mutants of BRAF cause cardio-facio-cutaneous (CFC) syndrome, characterized by growth and developmental defects, cardiac malformations, facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, the systemic BrafQ241R/+ mutant mouse, has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutations on neural function, separately from their effects on developmental processes. To this end, we generated Braf mutant mice expressing BRAFQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development. Behavioral analysis revealed that n-BrafQ241R/+ mice exhibited reduced home cage activity and learning disability, which were similar to those of systemic BrafQ241R/+ mice. The active form of ERK was increased in the hippocampus of n-BrafQ241R/+ mice, whereas basal synaptic transmission and synaptic plasticity in hippocampal Schaffer collateral-CA1 synapses seems to be normal. Transcriptome analysis of the hippocampal tissue revealed significant changes in the expression of genes involved in regulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, synaptic function and memory formation. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of the RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain. A similar mechanism may be possible in human CFC syndrome.

  15. Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants. International-journal

    Ayumi Nishiyama, Tetsuya Niihori, Naoki Suzuki, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Yoko Aoki, Masashi Aoki

    Neurology. Genetics　10　(6)　e200196　2024/12

    DOI： 10.1212/NXG.0000000000200196 　

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    BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated. METHODS: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes. RESULTS: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 ± 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression. DISCUSSION: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.

  16. Lymphatic endothelial cell-specific NRAS p.Q61R mutant embryos show abnormal lymphatic vessel morphogenesis. International-journal

    Akifumi Nozawa, Taiki Abe, Tetsuya Niihori, Michio Ozeki, Yoko Aoki, Hidenori Ohnishi

    Human molecular genetics　2024/05/13

    DOI： 10.1093/hmg/ddae080 　

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    Generalized lymphatic anomaly (GLA) and kaposiform lymphangiomatosis (KLA) are rare congenital disorders that arise through anomalous embryogenesis of the lymphatic system. A somatic activating NRAS p.Q61R variant has been recently detected in GLA and KLA tissues, suggesting that the NRAS p.Q61R variant plays an important role in the development of these diseases. To address this role, we studied the effect of the NRAS p.Q61R variant in lymphatic endothelial cells (LECs) on the structure of the lymphatics during embryonic and postnatal lymphangiogenesis applying inducible, LEC-specific NRAS p.Q61R variant in mice. Lox-stop-Lox NrasQ61R mice were crossed with Prox1-CreERT2 mice expressing tamoxifen-inducible Cre recombinase specifically in LECs. Whole-mount immunostaining of embryonic back skin using an antibody against the LEC surface marker VEGFR3 showed considerably greater lymphatic vessel width in LEC-specific NRAS p.Q61R mutant embryos than in littermate controls. These mutant embryos also showed a significant reduction in the number of lymphatic vessel branches. Furthermore, immunofluorescence staining of whole-mount embryonic back skin using an antibody against the LEC-specific nuclear marker Prox1 showed a large increase in the number of LECs in LEC-specific NRAS p.Q61R mutants. In contrast, postnatal induction of the NRAS p.Q61R variant in LECs did not cause abnormal lymphatic vessel morphogenesis. These results suggest that the NRAS p.Q61R variant in LECs plays a role in development of lymphatic anomalies. While this model does not directly reflect the human pathology of GLA and KLA, there are overlapping features, suggesting that further study of this model may help in studying GLA and KLA mechanisms.

  17. Case Report: An Adult Case of Poretti-Boltshauser Syndrome Diagnosed by Medical Checkup. International-journal

    Kensuke Ikeda, Ayane Tamagake, Takafumi Kubota, Rumiko Izumi, Tatsuo Yamaguchi, Kumiko Yanagi, Tatsuro Misu, Yoko Aoki, Tadashi Kaname, Masashi Aoki

    Cerebellum (London, England)　2024/02/29

    DOI： 10.1007/s12311-024-01673-2 　

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    This report describes an adult case of Poretti-Boltshauser syndrome (PTBHS) and with novel variants of LAMA1. A 65-year-old Japanese woman with cerebellar malformation identified during a medical checkup was referred to our hospital. Subsequently, neurological examination, brain imaging, and genetic investigation via whole-exome sequencing were performed. The patient presented with mild cerebellar ataxia and intellectual disability. Magnetic resonance imaging revealed cerebellar dysplasia and cysts and an absence of molar tooth sign. Genetic analysis revealed a novel homozygous variant of c.1711_1712del in LAMA1 (NM_005559.4). Most cases with PTBHS are reported in pediatric patients; however, our patient expressed a mild phenotype and was undiagnosed until her 60 s. These findings suggest that PTBHS should be considered in not only pediatric cerebellar dysplasia but also adult cerebellar ataxia with mild presentation.

  18. Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps. International-journal

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Yoshihiko Furusawa, Misa Nakano, Yasushi Oya, Kazuhiro Kato, Takuro Shiga, Kensuke Ikeda, Naoki Suzuki, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    Cerebellum (London, England)　2024/02/07

    DOI： 10.1007/s12311-024-01666-1 　

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    Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

  19. Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy. International-journal

    Rumiko Izumi, Kensuke Ikeda, Tetsuya Niihori, Naoki Suzuki, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki

    Annals of clinical and translational neurology　2023/12/29

    DOI： 10.1002/acn3.51977 　

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    OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3. METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues. RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs. INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.

  20. LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion. International-journal

    Taiki Abe, Shin-Ichiro Kanno, Tetsuya Niihori, Miho Terao, Shuji Takada, Yoko Aoki

    Cell death & disease　14　(8)　556-556　2023/08/25

    DOI： 10.1038/s41419-023-06072-9 　

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    Leucine zipper-like transcriptional regulator 1 (LZTR1), a substrate adaptor of Cullin 3 (CUL3)-based E3 ubiquitin ligase, regulates proteostasis of the RAS subfamily. Mutations in LZTR1 have been identified in patients with several types of cancer. However, the role of LZTR1 in tumor metastasis and the target molecules of LZTR1, excluding the RAS subfamily, are not clearly understood. Here, we show that LZTR1 deficiency increases tumor growth and metastasis. In lung adenocarcinoma cells, LZTR1 deficiency induced the accumulation of the RAS subfamily and enhanced cell proliferation, invasion, and xenograft tumor growth. Multi-omics analysis to clarify the pathways related to tumor progression showed that MAPK signaling, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling-related gene ontology terms were enriched in LZTR1 knockout cells. Indeed, LZTR1 deficiency induced high expression of EMT markers under TGF-β1 treatment. Our search for novel substrates that interact with LZTR1 resulted in the discovery of a Kelch-like protein 12 (KLHL12), which is involved in collagen secretion. LZTR1 could inhibit KLHL12-mediated ubiquitination of SEC31A, a component of coat protein complex II (COPII), whereas LZTR1 deficiency promoted collagen secretion. LZTR1-RIT1 and LZTR1-KLHL12 worked independently regarding molecular interactions and did not directly interfere with each other. Further, we found that LZTR1 deficiency significantly increases lung metastasis and promotes ECM deposition around metastatic tumors. Since collagen-rich extracellular matrix act as pathways for migration and facilitate metastasis, increased expression of RAS and collagen deposition may exert synergistic or additive effects leading to tumor progression and metastasis. In conclusion, LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and promoting collagen secretion. The functional inhibition of KLHL12 by LZTR1 provides important evidence that LZTR1 may be a repressor of BTB-Kelch family members. These results provide clues to the mechanism of LZTR1-deficiency carcinogenesis.

  21. Neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis: A case report with a novel missense variant of SCN1A. International-journal

    Yukimune Okubo, Moriei Shibuya, Haruhiko Nakamura, Aritomo Kawashima, Kaori Kodama, Wakaba Endo, Takehiko Inui, Noriko Togashi, Yu Aihara, Matsuyuki Shirota, Ryo Funayama, Tetsuya Niihori, Atsushi Fujita, Keiko Nakayama, Yoko Aoki, Naomichi Matsumoto, Shigeo Kure, Atsuo Kikuchi, Kazuhiro Haginoya

    Brain & development　2023/07/11

    DOI： 10.1016/j.braindev.2023.06.009 　

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    Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome. CASE REPORT: We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia. CONCLUSION: Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A. The efficacy of sodium channel blocker was also discussed. Further exploration of the phenotype-genotype relationship of SCN1A variants may lead to better pharmacological treatments and family guidance.

  22. CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Kodai Kume, Takashi Kurashige, Keiko Muguruma, Hiroyuki Morino, Yui Tada, Mai Kikumoto, Tatsuo Miyamoto, Silvia Natsuko Akutsu, Yukiko Matsuda, Shinya Matsuura, Masahiro Nakamori, Ayumi Nishiyama, Rumiko Izumi, Tetsuya Niihori, Masashi Ogasawara, Nobuyuki Eura, Tamaki Kato, Mamoru Yokomura, Yoshiaki Nakayama, Hidefumi Ito, Masataka Nakamura, Kayoko Saito, Yuichi Riku, Yasushi Iwasaki, Hirofumi Maruyama, Yoko Aoki, Ichizo Nishino, Yuishin Izumi, Masashi Aoki, Hideshi Kawakami

    American journal of human genetics　110　(7)　1086-1097　2023/06/20

    DOI： 10.1016/j.ajhg.2023.05.014 　

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.

  23. Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice. International-journal

    Koki Nagai, Tetsuya Niihori, Akihiko Muto, Yoshikazu Hayashi, Taiki Abe, Kazuhiko Igarashi, Yoko Aoki

    Blood advances　2023/04/26

    DOI： 10.1182/bloodadvances.2022008462 　

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    Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome characterized by congenital fusion of the forearm bones. RUSAT is largely caused by missense mutations that are clustered in a specific region of the MDS1 and EVI1 complex locus (MECOM). EVI1, a transcript variant encoded by MECOM, is a zinc finger transcription factor involved in hematopoietic stem cell maintenance that induce leukemic transformation when overexpressed. Mice with exonic deletions in Mecom show reduced hematopoietic stem and progenitor cells (HSPCs). However, the pathogenic roles of RUSAT-associated MECOM mutations in vivo have not yet been elucidated. To investigate the impact of the RUSAT-associated MECOM mutation on the phenotype, we generated knock-in mice harboring a point mutation (translated into EVI1 p.H752R and MDS1-EVI1 p.H942R), which corresponds to an EVI1 p.H751R and MDS1-EVI1 p.H939R mutation identified in a patient with RUSAT. Homozygous mutant mice died at embryonic day 10.5-11.5. Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis. Male Evi1KI/+ mice aged 5-15 weeks exhibited lower body weight and those aged 16 weeks and older showed low platelet counts. Flow cytometric analysis of bone marrow cells revealed a decrease in HSPCs in Evi1KI/+ mice at 8-12 weeks. Moreover, Evi1KI/+ mice showed delayed leukocyte and platelet recovery after 5-fluorouracil-induced myelosuppression. These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles.

  24. Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility. International-journal

    Maako Kawamura, Hidekazu Shirota, Tetsuya Niihori, Keigo Komine, Masanobu Takahashi, Shin Takahashi, Eisaku Miyauchi, Hidetaka Niizuma, Atsuo Kikuchi, Hiroshi Tada, Muneaki Shimada, Naoki Kawamorita, Masayuki Kanamori, Ikuko Sugiyama, Mari Tsubata, Hitotshi Ichikawa, Jun Yasuda, Toru Furukawa, Yoko Aoki, Chikashi Ishioka

    Journal of human genetics　68　(6)　399-408　2023/02/20

    DOI： 10.1038/s10038-023-01133-5 　

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    Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis.

  25. Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome.

    Masahiro Irie, Tetsuya Niihori, Tomohiro Nakano, Tasuku Suzuki, Saori Katayama, Kunihiko Moriya, Hidetaka Niizuma, Nobu Suzuki, Yuka Saito-Nanjo, Masaei Onuma, Takeshi Rikiishi, Atsushi Sato, Mayumi Hangai, Mitsuteru Hiwatari, Junji Ikeda, Reo Tanoshima, Norio Shiba, Yuki Yuza, Nobuyuki Yamamoto, Yoshiko Hashii, Motohiro Kato, Junko Takita, Miho Maeda, Yoko Aoki, Masue Imaizumi, Yoji Sasahara

    International journal of hematology　117　(4)　598-606　2022/12/14

    DOI： 10.1007/s12185-022-03505-7 　

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    Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.

  26. Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations. International-journal

    Akifumi Nozawa, Akihiro Fujino, Shunsuke Yuzuriha, Souichi Suenobu, Aiko Kato, Fumiaki Shimizu, Noriko Aramaki-Hattori, Kanako Kuniyeda, Kazuya Sakaguchi, Hidenori Ohnishi, Yoko Aoki, Michio Ozeki

    Journal of human genetics　67　(12)　721-728　2022/12

    DOI： 10.1038/s10038-022-01081-6 　

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    Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-flow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n  =  21, lymphatic malformations n  =  27, lymphatic venous malformations n  =  1, and Klippel-Trenaunay syndrome n  =  10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). In total, 37 of 59 patients (62.7%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.

  27. The molecular genetics of RASopathies: An update on novel disease genes and new disorders. International-journal

    Marco Tartaglia, Yoko Aoki, Bruce D Gelb

    American journal of medical genetics. Part C, Seminars in medical genetics　190　(4)　425-439　2022/11/16

    DOI： 10.1002/ajmg.c.32012 　

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    Enhanced signaling through RAS and the mitogen-associated protein kinase (MAPK) cascade underlies the RASopathies, a family of clinically related disorders affecting development and growth. In RASopathies, increased RAS-MAPK signaling can result from the upregulated activity of various RAS GTPases, enhanced function of proteins positively controlling RAS function or favoring the efficient transmission of RAS signaling to downstream transducers, functional upregulation of RAS effectors belonging to the MAPK cascade, or inefficient signaling switch-off operated by feedback mechanisms acting at different levels. The massive effort in RASopathy gene discovery performed in the last 20 years has identified more than 20 genes implicated in these disorders. It has also facilitated the characterization of several molecular activating mechanisms that had remained unappreciated due to their minor impact in oncogenesis. Here, we provide an overview on the discoveries collected during the last 5 years that have delivered unexpected insights (e.g., Noonan syndrome as a recessive disease) and allowed to profile new RASopathies, novel disease genes and new molecular circuits contributing to the control of RAS-MAPK signaling.

  28. Clinical decisions by the molecular tumor board on comprehensive genomic profiling tests in Japan: A retrospective observational study. International-journal

    Hidekazu Shirota, Keigo Komine, Masanobu Takahashi, Shin Takahashi, Eisaku Miyauchi, Hidetaka Niizuma, Hiroshi Tada, Muneaki Shimada, Tetsuya Niihori, Yoko Aoki, Ikuko Sugiyama, Maako Kawamura, Jun Yasuda, Shuhei Suzuki, Takeshi Iwaya, Motonobu Saito, Tsuyoshi Saito, Hiroyuki Shibata, Toru Furukawa, Chikashi Ishioka

    Cancer medicine　12　(5)　6170-6181　2022/10/17

    DOI： 10.1002/cam4.5349 　

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    BACKGROUND: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions. METHODS: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations. RESULTS: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%). CONCLUSION: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

  29. Noonan症候群類縁疾患を有する児を育てる養育者の心理社会的側面に関する実態調査

    小野 智愛, 新堀 哲也, 深見 真紀, 黒澤 健司, 大橋 博文, 岡本 伸彦, 水野 誠司, 緒方 勤, 松原 洋一, 津幡 真理, 川村 真亜子, 川目 裕, 青木 洋子

    日本遺伝カウンセリング学会誌　43　(3)　143-154　2022/10

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  30. 遺伝性腫瘍リスク評価における問診票の有効性と心理社会的要因の検討

    津幡 真理, 新堀 哲也, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 金澤 麻衣子, 吉田 沙蘭, 石田 孝宣, 青木 洋子

    日本遺伝カウンセリング学会誌　43　(3)　121-130　2022/10

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  31. 病的バリアントと確定しがたいdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 戸恒 智子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 吉岡 勝, 馬場 徹, 大泉 英樹, 田中 洋康, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　62　(Suppl.)　S221-S221　2022/10

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  32. A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor. International-journal

    Yu Aihara, Matsuyuki Shirota, Atsuo Kikuchi, Yu Katata, Yu Abe, Tetsuya Niihori, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Shigeo Kure

    Journal of human genetics　2022/09/27

    DOI： 10.1038/s10038-022-01082-5 　

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    ANO3 encodes Anoctamin-3, also known as TMEM16C, a calcium-activated chloride channel. Heterozygous variants of ANO3 can cause dystonia 24, an adult-onset focal dystonia. Some pediatric cases have been reported, but most patients were intellectually normal with some exceptions. Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia. Trio exome sequencing identified a heterozygous de novo missense variant NM_031418.4:c.1809T>G, p.(Asn603Lys) in the ANO3 gene. Three cases with ANO3 variants and intellectual disability have been reported, including the present case. These variants were predicted to face in the same direction on the same alpha-helix (the transmembrane 4 domain), suggesting an association between these variants and childhood-onset movement disorder with intellectual disability. In pediatric cases with developmental delay and movement disorders such as tremor and ataxia, specific variants in the transmembrane 4 domain of ANO3 may be a cause, even in the absence of dystonia.

  33. Returning individual genomic results to population-based cohort study participants with BRCA1/2 pathogenic variants.

    Kinuko Ohneda, Yohei Hamanaka, Hiroshi Kawame, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Yumi Yamaguchi-Kabata, Muneaki Shimada, Atsushi Masamune, Yoko Aoki, Takanori Ishida, Masayuki Yamamoto

    Breast cancer (Tokyo, Japan)　30　(1)　110-120　2022/09/26

    DOI： 10.1007/s12282-022-01404-7 　

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    BACKGROUND: Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. METHODS: Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. RESULTS: All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. CONCLUSIONS: Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

  34. 全ゲノム/全エキソーム解析による生殖細胞系列多型の探索 一般住民コホートにおけるBRCA遺伝子バリアントの探索及び結果の回付事業について(Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants)

    徳永 英樹, 安田 純, 島田 宗昭, 濱中 洋平, 重田 昌吾, 布施 昇男, 勝岡 史城, 荻島 創一, 山口 由美, 寳澤 篤, 川目 裕, 大根田 絹子, 青木 洋子, 山本 雅之, 八重樫 伸生

    日本癌学会総会記事　81回　S8-1　2022/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  35. Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14). International-journal

    Mari Minatogawa, Ai Unzaki, Hiroko Morisaki, Delfien Syx, Tohru Sonoda, Andreas R Janecke, Anne Slavotinek, Nicol C Voermans, Yves Lacassie, Roberto Mendoza-Londono, Klaas J Wierenga, Parul Jayakar, William A Gahl, Cynthia J Tifft, Luis E Figuera, Yvonne Hilhorst-Hofstee, Alessandra Maugeri, Ken Ishikawa, Tomoko Kobayashi, Yoko Aoki, Toshihiro Ohura, Hiroshi Kawame, Michihiro Kono, Kosuke Mochida, Chiho Tokorodani, Kiyoshi Kikkawa, Takayuki Morisaki, Tetsuyuki Kobayashi, Takaya Nakane, Akiharu Kubo, Judith D Ranells, Ohsuke Migita, Glenda Sobey, Anupriya Kaur, Masumi Ishikawa, Tomomi Yamaguchi, Naomichi Matsumoto, Fransiska Malfait, Noriko Miyake, Tomoki Kosho

    Journal of medical genetics　59　(9)　865-877　2022/09

    DOI： 10.1136/jmedgenet-2020-107623 　

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    BACKGROUND: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. METHODS: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. RESULTS: Sixty-six patients in 48 families (33 males/females; 0-59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype-phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. CONCLUSION: This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

  36. Severe neuroglycopenic symptoms due to nonketotic hypoglycemia in children with cardio-facio-cutaneous syndrome. International-journal

    Tadashi Shiohama, Katsunori Fujii, Rika Kosaki, Yoshimi Watanabe, Tomoko Uchida, Sho Hagiwara, Kaori Kinoshita, Katsuo Sugita, Yoko Aoki, Naoki Shimojo

    American journal of medical genetics. Part A　188　(12)　3505-3509　2022/08/09

    DOI： 10.1002/ajmg.a.62926 　

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    Cardio-facio-cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4-year-old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3-year-old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left-hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2-elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co-occurrence of mitochondrial HMG-CoA synthase deficiency and HMG-CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia.

  37. The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery. International-journal

    Maria I Kontaridis, Amy E Roberts, Lisa Schill, Lisa Schoyer, Beth Stronach, Gregor Andelfinger, Yoko Aoki, Marni E Axelrad, Annette Bakker, Anton M Bennett, Alberto Broniscer, Pau Castel, Caitlin A Chang, Lukas Cyganek, Tirtha K Das, Jeroen den Hertog, Emilia Galperin, Shruti Garg, Bruce D Gelb, Kristiana Gordon, Tamar Green, Karen W Gripp, Maxim Itkin, Maija Kiuru, Bruce R Korf, Jeff R Livingstone, Alejandro López-Juárez, Pilar L Magoulas, Sahar Mansour, Theresa Milner, Elisabeth Parker, Elizabeth I Pierpont, Kevin Plouffe, Katherine A Rauen, Suma P Shankar, Shane B Smith, David A Stevenson, Marco Tartaglia, Richard Van, Morgan E Wagner, Stephanie M Ware, Martin Zenker

    American journal of medical genetics. Part A　188　(6)　1915-1927　2022/06

    DOI： 10.1002/ajmg.a.62716 　

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    RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

  38. Novel POLE mutations identified in patients with IMAGE-I syndrome cause aberrant subcellular localisation and protein degradation in the nucleus. International-journal

    Tomohiro Nakano, Yoji Sasahara, Atsuo Kikuchi, Kunihiko Moriya, Hidetaka Niizuma, Tetsuya Niihori, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Shigeo Kure

    Journal of medical genetics　59　(11)　1116-22　2022/05/09

    DOI： 10.1136/jmedgenet-2021-108300 　

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    BACKGROUND: DNA replisome is a molecular complex that plays indispensable roles in normal DNA replication. IMAGE-I syndrome is a DNA replisome-associated genetic disease caused by biallelic mutations in the gene encoding DNA polymerase epsilon catalytic subunit 1 (POLE). However, the underlying molecular mechanisms remain largely unresolved. METHODS: The clinical manifestations in two patients with IMAGE-I syndrome were characterised. Whole-exome sequencing was performed and altered mRNA splicing and protein levels of POLE were determined. Subcellular localisation, cell cycle analysis and DNA replication stress were assessed using fibroblasts and peripheral blood from the patients and transfected cell lines to determine the functional significance of POLE mutations. RESULTS: Both patients presented with growth retardation, adrenal insufficiency, immunodeficiency and complicated diffuse large B-cell lymphoma. We identified three novel POLE mutations: namely, a deep intronic mutation, c.1226+234G>A, common in both patients, and missense (c.2593T>G) and in-frame deletion (c.711_713del) mutations in each patient. The unique deep intronic mutation produced aberrantly spliced mRNAs. All mutants showed significantly reduced, but not null, protein levels. Notably, the mutants showed severely diminished nuclear localisation, which was rescued by proteasome inhibitor treatment. Functional analysis revealed impairment of cell cycle progression and increase in the expression of phospho-H2A histone family member X in both patients. CONCLUSION: These findings provide new insights regarding the mechanism via which POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression, a characteristic of DNA replisome-associated diseases.

  39. Cardiac features of Noonan syndrome in Japanese patients. International-journal

    Yasuhiro Ichikawa, Hiroyuki Kuroda, Takeshi Ikegawa, Shun Kawai, Shin Ono, Ki-Sung Kim, Sadamitsu Yanagi, Kenji Kurosawa, Yoko Aoki, Hideaki Ueda

    Cardiology in the young　1-6　2022/04/27

    DOI： 10.1017/S104795112200124X 　

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    BACKGROUND: Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome. METHODS: This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome. RESULTS: Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found in PTPN11 (25/43). The second and third most prevalent causative genes were SOS1 (6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations in PTPN11 (8/25), SOS1 (4/6), and RIT1 (4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations in RAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or without PTPN11 mutations. The proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit. CONCLUSIONS: These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.

  40. A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants.

    Kinuko Ohneda, Masahiro Hiratsuka, Hiroshi Kawame, Fuji Nagami, Yoichi Suzuki, Kichiya Suzuki, Akira Uruno, Mika Sakurai-Yageta, Yohei Hamanaka, Makiko Taira, Soichi Ogishima, Shinichi Kuriyama, Atsushi Hozawa, Hiroaki Tomita, Naoko Minegishi, Junichi Sugawara, Inaho Danjoh, Tomohiro Nakamura, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Shu Tadaka, Taku Obara, Eiji Hishimuma, Nariyasu Mano, Masaki Matsuura, Yuji Sato, Masateru Nakasone, Yohei Honkura, Jun Suzuki, Yukio Katori, Yoichi Kakuta, Atsushi Masamune, Yoko Aoki, Masaharu Nakayama, Shigeo Kure, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto

    JMA journal　5　(2)　177-189　2022/04/15

    DOI： 10.31662/jmaj.2021-0156 　

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    Introduction: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. Methods: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. Results: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. Conclusions: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.

  41. Current status and issues related to secondary findings in the first public insurance covered tumor genomic profiling in Japan: multi-site questionnaire survey. International-journal

    Akari Minamoto, Takahiro Yamada, Saki Shimada, Ichiro Kinoshita, Yoko Aoki, Katsutoshi Oda, Arisa Ueki, Satomi Higashigawa, Maki Morikawa, Yuki Sato, Akira Hirasawa, Masanobu Ogawa, Tomohiro Kondo, Masahiro Yoshioka, Masashi Kanai, Manabu Muto, Shinji Kosugi

    Journal of human genetics　67　(10)　557-563　2022/03/23

    DOI： 10.1038/s10038-022-01028-x 　

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    In June 2019, the Japanese National Health Insurance (NHI) system introduced coverage for two types of tumor genomic profiling (TGP): FoundationOneⓇ CDx (F1) and OncoGuide™ NCC OncoPanel System (NCCOP). TGP sometimes reveals germline variants that are potentially pathogenic as secondary findings (SFs). We conducted a questionnaire-based survey to find out the operational statuses of F1 and NCCOP at institutions where TGP was performed to elucidate issues related to SFs. Responses were received from 97 of 112 institutions (86.6%). As of May 31, 2020, 88 (90.7%) and 78 (80.4%) institutions started performing F1 and NCCOP, respectively. Since F1 only examines tumor samples, germline confirmatory testing is necessary to determine whether they are actually germline pathogenic variants (GPVs). When physicians are obtaining informed consent all but 2.3% of the patients requested SF disclosure. Conversely, when presumed germline pathogenic variants (PGPVs) were detected, 46.2% were not willing to receive confirmatory tests as they wanted to prioritize cancer treatment over SFs investigation, while only 23.3% underwent confirmatory tests. Problems in cancer genomic medicine reported by clinical genetics departments included short-staffing (n = 10), insufficient interdepartmental cooperation (n = 9), inconsistent understanding of genetics among healthcare professionals (n = 8), and low utilization rate of SFs due to lack of insurance coverage for confirmatory tests and post-test health checkups (n = 8). Solutions include; determining the appropriate timing to confirm patient intent on SF disclosure, covering confirmatory tests for PGPVs by the NHI, and establishing cooperation between the oncology and clinical genetics departments.

  42. A novel 8.57-kb deletion of the upstream region of PRKAR1A in a family with Carney complex. International-journal

    Shin Ito, Aya Hashimoto, Kazunori Yamaguchi, Sadafumi Kawamura, Shingo Myoen, Maki Ogawa, Ikuro Sato, Takamichi Minato, Shingo Miyabe, Akira Nakazato, Keitaro Fujii, Mai Mochizuki, Haruna Fujimori, Keiichi Tamai, Tetsuya Niihori, Yoko Aoki, Akira Sugawara, Hironobu Sasano, Hiroshi Shima, Jun Yasuda

    Molecular genetics & genomic medicine　10　(3)　e1884　2022/03

    DOI： 10.1002/mgg3.1884 　

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    Carney complex (CNC) is a rare hereditary syndrome that involves endocrine dysfunction and the development of various types of tumors. Chromosome 2p16 and PRKAR1A on chromosome 17 are known susceptibility loci for CNC. Here we report a mother and son with CNC caused by an 8.57-kb deletion involving the transcription start site and non-coding exon 1 of PRKAR1A. The proband is a 28-year-old male with bilateral large-cell calcified Sertoli cell testicular tumors and pituitary adenoma. Comprehensive genomic profiling for cancer mutations using Foundation One CDx failed to detect any mutations in PRKAR1A in DNA from the testicular tumor. Single-nucleotide polymorphism array analysis of the proband's genomic DNA revealed a large deletion in the 5' region of PRKAR1A. Genomic walking further delineated the region an 8.57-kb deletion. A 1.68-kb DNA fragment encompassed by the deleted region showed strong promoter activity in a NanoLuc luciferase reporter assay. The patient's mother, who is suffering from recurrent cardiac myxoma, a critical sign for CNC, carried an identical deletion. The 8.57-kb deleted region is a novel lesion for CNC and will facilitate molecular diagnosis of the disease.

  43. A rare pediatric case of McCune-Albright syndrome with acute visual disturbance: Case report. International-journal

    Hiroshi Ninomiya, Michio Ozeki, Akifumi Nozawa, Shiho Yasue, Saori Endo, Masayuki Inuzuka, Natsuko Obara, Kiyofumi Mochizuki, Masaya Kawaguchi, Yo Kaneko, Naoyuki Ohe, Yoko Aoki, Masayuki Matsuo, Toru Iwama, Hidenori Ohnishi

    Medicine　101　(6)　e28815　2022/02/11

    DOI： 10.1097/MD.0000000000028815 　

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    RATIONALE: McCune-Albright syndrome (MAS) is a rare disorder characterized by clinical findings, which includes fibrous dysplasia (FD). FD is a benign tumor that leads to increased rates of bone fracture. In some MAS cases with FD, facial deformities, severe pain, and orbital neuropathies are complicated. Aneurysmal bone cyst (ABC) is a benign bone tumor and rare complication of FD. PATIENT CONCERNS: A 9-year-old boy was admitted to our hospital because of acute visual disturbance. DIAGNOSIS AND INTERVENTIONS: The patient was clinically diagnosed as ABC complicated with MAS, and he underwent surgery. OUTCOMES: After the surgery, his sight became normal. Recurrence of ABC and visual disturbance was not observed in 3 years. Genetic analysis of a tissue sample from the ABC lesion by next-generation sequencing revealed a somatic activating GNAS mutation. LESSONS: To the best of our knowledge, this is the first case report of MAS causing optic neuropathy complicated with ABC. ABC complicated with MAS is extremely rare, but it should be considered as a possible diagnosis in patients with acute visual loss and facial swelling. In addition, our case had OAS, which is an uncommon syndrome and a rare complication in ABC with MAS, and rapid decompression of the ABC was effective in improving the patient's eyesight.

  44. Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. International-journal

    Miyako Kanno, Mitsuyoshi Suzuki, Ken Tanikawa, Chikahiko Numakura, Shu-Ichi Matsuzawa, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Satoshi Makino, Gen Tamiya, Satoshi Nakano, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuo Mitsui, Kiyoshi Hayasaka

    Journal of human genetics　67　(7)　393-397　2022/01/28

    DOI： 10.1038/s10038-022-01017-0 　

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    Paucity of interlobular bile ducts (PILBD) is a heterogeneous disorder classified into two categories, syndromic and non-syndromic bile duct paucity. Syndromic PILBD is characterized by the presence of clinical manifestations of Alagille syndrome. Non-syndromic PILBD is caused by multiple diseases, such as metabolic and genetic disorders, infectious diseases, and inflammatory and immune disorders. We evaluated a family with a dominantly inherited PILBD, who presented with cholestasis at 1-2 months of age but spontaneously improved by 1 year of age. Next-generation sequencing analysis revealed a heterozygous CACYBP/SIP p.E177Q pathogenic variant. Calcyclin-binding protein and Siah1 interacting protein (CACYBP/SIP) form a ubiquitin ligase complex and induce proteasomal degradation of non-phosphorylated β-catenin. Immunohistochemical analysis revealed a slight decrease in CACYBP and β-catenin levels in the liver of patients in early infancy, which almost normalized by 13 months of age. The CACYBP/SIP p.E177Q pathogenic variant may form a more active or stable ubiquitin ligase complex that enhances the degradation of β-catenin and delays the maturation of intrahepatic bile ducts. Our findings indicate that accurate regulation of the β-catenin concentration is essential for the development of intrahepatic bile ducts and CACYBP/SIP pathogenic variant is a novel cause of PILDB.

  45. Phenotypic heterogeneity in individuals with MECOM variants in 2 families. International-journal

    Tetsuya Niihori, Reo Tanoshima, Yoji Sasahara, Atsushi Sato, Masahiro Irie, Yuka Saito-Nanjo, Ryo Funayama, Matsuyuki Shirota, Taiki Abe, Yuko Okuyama, Naoto Ishii, Keiko Nakayama, Shigeo Kure, Masue Imaizumi, Yoko Aoki

    Blood advances　6　(18)　5257-5261　2022/01/12

    DOI： 10.1182/bloodadvances.2020003812 　

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    MECOM encodes the transcriptional regulators, EVI1 and MDS1-EVI1, from two distinct transcription start sites. EVI1 plays important roles in hematopoiesis and stem cell self-renewal. Recently, our group and others revealed that individuals with MECOM variants present diverse hematological and skeletal defects, including radioulnar synostosis (RUS). In the present study, we analyzed two families suspected with MECOM-associated syndrome. In family 1, a MECOM splicing variant (c.2285+1G>A) was identified in an individual with bone marrow failure (TRS4) without RUS and her mother, who had mild leukocytopenia, thrombocytopenia, and bilateral RUS. A copy neutral loss of heterozygosity decreasing the variant allele frequency was observed in the bone marrow of TRS4 and the peripheral blood leukocytes of her mother. However, TRS4 remained transfusion-dependent. In family 2, a MECOM variant (c.2208-4A>G), which was predicted to cause a cryptic acceptor site that results in a 3-base insertion (an insertion of Ser) in the mRNA, was identified in the proband, with bone marrow failure; this variant was also observed in her brother and father, both of whom have skeletal malformations, but no cytopenia. RT-PCR using leukocytes revealed a transcript with a 3-bp insertion in the proband, her brother, and the father, suggesting that the transcript variant with a 3-bp insertion is independent of blood phenotype. Collectively, these results suggest the presence of intrafamilial clinical heterogeneity in both families with MECOM splicing variants. Somatic genetic event may complicate the understanding of clinical variability among family members.

  46. Multidisciplinary Management of Costello Syndrome: Current Perspectives. International-journal

    Chiara Leoni, Germana Viscogliosi, Marco Tartaglia, Yoko Aoki, Giuseppe Zampino

    Journal of multidisciplinary healthcare　15　1277-1296　2022

    DOI： 10.2147/JMDH.S291757 　

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    Costello syndrome (CS) is a rare neurodevelopmental disorder caused by germline mutations in HRAS. It belongs among the RASopathies, a group of syndromes characterized by alterations in components of the RAS/MAPK signaling pathway and sharing overlapping phenotypes. Its typical features include a distinctive facial appearance, growth delay, intellectual disability, ectodermal, cardiac, and musculoskeletal abnormalities, and cancer predisposition. Due to the several comorbidities having a strong impact on the quality of life, a multidisciplinary team is essential in the management of such a condition from infancy to adult age, to promptly address any detected issue and to develop appropriate personalized follow-up protocols and treatment strategies. With the present paper we aim to highlight the core and ancillary medical disciplines involved in managing the health challenges characterizing CS from pediatric to adult age, according to literature and to our large clinical experience.

  47. Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome. International-journal

    Koki Nagai, Tetsuya Niihori, Nobuhiko Okamoto, Akane Kondo, Kenichi Suga, Tomoko Ohhira, Yasunobu Hayabuchi, Yukako Homma, Ryuji Nakagawa, Toshinobu Ifuku, Taiki Abe, Takeshi Mizuguchi, Naomichi Matsumoto, Yoko Aoki

    Human mutation　43　(1)　3-15　2021/10/07

    DOI： 10.1002/humu.24287 　

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    Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

  48. LSS欠損症における組織特異的モデルマウスを用いた代謝および病理プロファイル

    和田 陽一, 菊池 敦生, 加賀 元宗, 清水 直紀, 伊藤 隼哉, 新堀 哲也, 佐藤 孝太, 中澤 徹, 中山 啓子, 青木 洋子, 仲川 清隆, 呉 繁夫

    日本先天代謝異常学会雑誌　37　126-126　2021/09

    Publisher: (一社)日本先天代謝異常学会

    ISSN： 0912-0122

  49. The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project. International-journal

    Hiroshi Kawame, Akimune Fukushima, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Mika Sakurai-Yageta, Jun Yasuda, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Soichi Ogishima, Takako Takai, Shinichi Kuriyama, Atsushi Hozawa, Naoki Nakaya, Tomohiro Nakamura, Naoko Minegishi, Junichi Sugawara, Kichiya Suzuki, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Yayoi Aizawa, Tomoharu Tokutomi, Kayono Yamamoto, Kinuko Ohneda, Shigeo Kure, Yoko Aoki, Hideki Katagiri, Yasushi Ishigaki, Shojiro Sawada, Makoto Sasaki, Masayuki Yamamoto

    Journal of human genetics　67　(1)　9-17　2021/07/08

    DOI： 10.1038/s10038-021-00952-8 　

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    Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

  50. 遺伝性腫瘍リスク評価における問診票とインタビュー調査の有効性の検討

    津幡 真理, 新堀 哲也, 永井 康貴, 野澤 明史, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 金澤 麻衣子, 石田 孝宣, 青木 洋子

    日本遺伝カウンセリング学会誌　42　(2)　71-71　2021/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  51. Characterization of kaposiform lymphangiomatosis tissue-derived cells. International-journal

    Akifumi Nozawa, Michio Ozeki, Shiho Yasue, Saori Endo, Kei Noguchi, Tomohiro Kanayama, Hiroyuki Tomita, Yoko Aoki, Hidenori Ohnishi

    Pediatric blood & cancer　68　(10)　e29086　2021/04/29

    DOI： 10.1002/pbc.29086 　

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    BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a recently characterized systemic lymphatic anomaly. Activation of RAS/MAPK and PI3K/AKT/mTOR pathways may affect KLA pathogenesis, but the cellular basis of KLA is unclear. Abnormal-spindle endothelial cells that express lymphatic endothelial cell (LEC) markers are characteristic of KLA histopathology. This study evaluated patient-derived KLA cells to establish their morphological and biological characteristics. PROCEDURE: We established cell lines from primary KLA tissues of two patients with KLA and examined their morphological and functional characteristics, messenger RNA and protein expression profiles, gene mutations, and responses to inhibitors of the RAS/MAPK and PI3K/AKT/mTOR pathways. RESULTS: Both KLA cell lines showed spindle-shaped morphology, stained positive for podoplanin (PDPN), and exhibited impaired tube-formation properties. They expressed LEC marker PDPN and mesenchymal stem cell markers (CD90, CD105) in the absence of endothelial cell markers (CD34, CD31, VWF), per real-time polymerase chain reaction. Both mTOR inhibitor rapamycin and MEK inhibitor trametinib inhibited growth of the two cell lines. A NRAS p.Q61R variant was found in one of two independent KLA tissue samples, but not in the KLA cells (per targeted next-generation sequencing); and KLA cells with this variant had elevated AKT phosphorylation levels. ERK phosphorylation levels were undetectable in both KLA cell lines. CONCLUSIONS: Inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways may represent potential therapeutic targets in KLA. These patient-derived KLA cell lines will be useful research tools to elucidate KLA etiology, and could pave the way for basic, translational, and preclinical studies of this disease.

  52. Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans. International-journal

    Angelica Gualtieri, Nikolina Kyprianou, Louise C Gregory, Maria Lillina Vignola, James G Nicholson, Rachael Tan, Shin-Ichi Inoue, Valeria Scagliotti, Pedro Casado, James Blackburn, Fernando Abollo-Jimenez, Eugenia Marinelli, Rachael E J Besser, Wolfgang Högler, I Karen Temple, Justin H Davies, Andrey Gagunashvili, Iain C A F Robinson, Sally A Camper, Shannon W Davis, Pedro R Cutillas, Evelien F Gevers, Yoko Aoki, Mehul T Dattani, Carles Gaston-Massuet

    Nature communications　12　(1)　2028-2028　2021/04/01

    DOI： 10.1038/s41467-021-21712-4 　

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    Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

  53. A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy. International-journal

    Aya Inoue-Shibui, Tetsuya Niihori, Michio Kobayashi, Naoki Suzuki, Rumiko Izumi, Hitoshi Warita, Kenju Hara, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Ichizo Nishino, Masashi Aoki, Yoko Aoki

    Journal of human genetics　66　(10)　965-972　2021/03/20

    DOI： 10.1038/s10038-021-00916-y 　

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    Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.

  54. A Patient with Noonan Syndrome with a KRAS Mutation Who Presented Severe Nerve Root Hypertrophy

    Yoshihito Ando, Mikio Sawada, Tadataka Kawakami, Mitsuya Morita, Yoko Aoki

    Case Reports in Neurology　13　(1)　108-118　2021/02/16

    Publisher: S. Karger AG

    DOI： 10.1159/000512265 　

    eISSN： 1662-680X

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    We report a 45-year-old female with clinical features resembling Noonan syndrome (NS) who presented with significant nerve root hypertrophy. She was initially diagnosed with Charcot-Marie-Tooth disease because her gait disturbance gradually deteriorated and nerve conduction velocity was reduced. However, she did not carry a <i>PMP22</i> gene mutation. RASopathies are a group of phenotypically overlapping developmental syndromes caused by germline mutations that encode components of the Ras/MAPK signaling pathway. These disorders include NS, cardiofaciocutaneous (CFC) syndrome, and Costello syndrome and are associated with molecular abnormalities in the Ras/MAPK pathway. The patient was suspected to have NS and related disorders because of pulmonary artery stenosis, lymphedema, distinctive facial appearance, and intellectual disability. Genetic analysis identified a heterozygous de novo mutation in <i>KRAS</i> (c.211T>G, p.Tyr71Asp), which is usually observed in patients with NS or CFC syndrome. Although our patient was diagnosed with NS, she revealed clinical manifestations that were typical to CFC syndrome, including intellectual disability. It has been reported that some patients diagnosed with RASopathies with mutations in <i>PTPN11</i>, <i>SOS1</i>, or <i>KRAS</i> developed nerve root hypertrophy. These results suggest that nerve root hypertrophy may be associated with RASopathy, although the onset mechanisms of nerve root hypertrophy are unknown.

  55. Possible Somatic Mosaicism of Novel FUS Variant in Familial Amyotrophic Lateral Sclerosis. International-journal

    Shin Hisahara, Ayumi Nishiyama, Emiko Tsuda, Syuuichirou Suzuki, Akihiro Matsumura, Aki Ishikawa, Akihiro Sakurai, Ikuko N Motoike, Masashi Aoki, Yoko Aoki, Shun Shimohama

    Neurology. Genetics　7　(1)　e552　2021/02

    DOI： 10.1212/NXG.0000000000000552 　

  56. Costello syndrome model mice with a HrasG12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis. International-journal

    Yu Katata, Shin-Ichi Inoue, Atsuko Asao, Shuhei Kobayashi, Hitoshi Terui, Aya Inoue-Shibui, Taiki Abe, Tetsuya Niihori, Setsuya Aiba, Naoto Ishii, Shigeo Kure, Yoko Aoki

    Cell death & disease　11　(8)　617-617　2020/08/13

    DOI： 10.1038/s41419-020-02845-8 　

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    Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.

  57. Correction: Biallelic GALM pathogenic variants cause a novel type of galactosemia. International-journal

    Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

    Genetics in medicine : official journal of the American College of Medical Genetics　22　(7)　1281-1281　2020/07

    DOI： 10.1038/s41436-020-0836-z 　

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  58. 当院で行った遺伝性出血性毛細血管拡張症(HHT)に関する遺伝カウンセリング

    津幡 真理, 新堀 哲也, 永井 康貴, 井上 彩, 野澤 明史, 青木 洋子

    日本遺伝カウンセリング学会誌　41　(2)　66-66　2020/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  59. The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype-phenotype relationship and a hotspot on the inner DysF domain. International-journal Peer-reviewed

    Rumiko Izumi, Toshiaki Takahashi, Naoki Suzuki, Tetsuya Niihori, Hiroya Ono, Naoko Nakamura, Shinichi Katada, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki

    Human mutation　41　(9)　1540-1554　2020/05/12

    DOI： 10.1002/humu.24036 　

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    Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

  60. Japanese Clinical Practice Guidelines for Vascular Anomalies 2017. International-journal Peer-reviewed

    Hidefumi Mimura, Sadanori Akita, Akihiro Fujino, Masatoshi Jinnin, Mine Ozaki, Keigo Osuga, Hiroki Nakaoka, Eiichi Morii, Akira Kuramochi, Yoko Aoki, Yasunori Arai, Noriko Aramaki, Masanori Inoue, Yuki Iwashina, Tadashi Iwanaka, Shigeru Ueno, Akihiro Umezawa, Michio Ozeki, Junko Ochi, Yoshiaki Kinoshita, Masakazu Kurita, Shien Seike, Nobuyuki Takakura, Masataka Takahashi, Takao Tachibana, Kumiko Chuman, Shuji Nagata, Mitsunaga Narushima, Yasunari Niimi, Shunsuke Nosaka, Taiki Nozaki, Kazuki Hashimoto, Ayato Hayashi, Satoshi Hirakawa, Atsuko Fujikawa, Yumiko Hori, Kentaro Matsuoka, Hideki Mori, Yuki Yamamoto, Shunsuke Yuzuriha, Naoaki Rikihisa, Shoji Watanabe, Shinichi Watanabe, Tatsuo Kuroda, Shunsuke Sugawara, Kosuke Ishikawa, Satoru Sasaki

    The Journal of dermatology　47　(5)　e138-e183　2020/05

    DOI： 10.1111/1346-8138.15189 　

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    The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety and systematizing treatment, employing evidence-based medicine techniques and aimed at improvement of the outcomes. Clinical questions (CQ) were decided based on the important clinical issues. For document retrieval, key words for published work searches were set for each CQ, and work published from 1980 to the end of September 2014 was searched in PubMed, Cochrane Library and Japana Centra Revuo Medicina databases. The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System technique. A total of 33 CQ were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

  61. Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. International-journal Peer-reviewed

    Atsushi Masamune, Hiroshi Kotani, Franziska Lena Sörgel, Jian-Min Chen, Shin Hamada, Reiko Sakaguchi, Emmanuelle Masson, Eriko Nakano, Yoichi Kakuta, Tetsuya Niihori, Ryo Funayama, Matsuyuki Shirota, Tatsuya Hirano, Tetsuya Kawamoto, Atsuki Hosokoshi, Kiyoshi Kume, Lara Unger, Maren Ewers, Helmut Laumen, Peter Bugert, Masayuki X Mori, Volodymyr Tsvilovskyy, Petra Weißgerber, Ulrich Kriebs, Claudia Fecher-Trost, Marc Freichel, Kalliope N Diakopoulos, Alexandra Berninger, Marina Lesina, Kentaro Ishii, Takao Itoi, Tsukasa Ikeura, Kazuichi Okazaki, Tom Kaune, Jonas Rosendahl, Masao Nagasaki, Yasuhito Uezono, Hana Algül, Keiko Nakayama, Yoichi Matsubara, Yoko Aoki, Claude Férec, Yasuo Mori, Heiko Witt, Tooru Shimosegawa

    Gastroenterology　158　(6)　1626-1641　2020/05

    DOI： 10.1053/j.gastro.2020.01.005 　

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    BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.

  62. Double-chambered right ventricle complicated by hypertrophic obstructive cardiomyopathy diagnosed as Noonan syndrome. International-journal

    Masahiro Yamamoto, Seiji Takashio, Naoya Nakashima, Shinsuke Hanatani, Yuichiro Arima, Kenji Sakamoto, Eiichiro Yamamoto, Koichi Kaikita, Yoko Aoki, Kenichi Tsujita

    ESC heart failure　7　(2)　721-726　2020/04

    DOI： 10.1002/ehf2.12650 　

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    We present a case of double-chambered right ventricle (DCRV) complicated by hypertrophic obstructive cardiomyopathy (HOCM) in KRAS mutation-associated Noonan syndrome. The diagnosis was incidental and made during diagnostic testing for an intradural extramedullary tumour. Spinal compression, if not surgically treated, may cause paralysis of the extremities. We decided to pursue pharmacological therapy to control biventricular obstructions and reduce the perioperative complication rate. We initiated treatment with cibenzoline and bisoprolol; the doses were titrated according to the response. After 2 weeks, the peak pressure gradient of the two RV chambers decreased from 101 to 68 mmHg, and the LV peak pressure gradient decreased from 109 to 14 mmHg. Class 1A antiarrhythmic drugs and β-blockers decreased the severe pressure gradients of biventricular obstructions caused by DCRV and HOCM. The patient was able to undergo surgery to remove the intradural extramedullary tumour, which was diagnosed as schwannoma.

  63. Japanese clinical practice guidelines for vascular anomalies 2017. Peer-reviewed

    Hidefumi Mimura, Sadanori Akita, Akihiro Fujino, Masatoshi Jinnin, Mine Ozaki, Keigo Osuga, Hiroki Nakaoka, Eiichi Morii, Akira Kuramochi, Yoko Aoki, Yasunori Arai, Noriko Aramaki, Masanori Inoue, Yuki Iwashina, Tadashi Iwanaka, Shigeru Ueno, Akihiro Umezawa, Michio Ozeki, Junko Ochi, Yoshiaki Kinoshita, Masakazu Kurita, Shien Seike, Nobuyuki Takakura, Masataka Takahashi, Takao Tachibana, Kumiko Chuman, Shuji Nagata, Mitsunaga Narushima, Yasunari Niimi, Shunsuke Nosaka, Taiki Nozaki, Kazuki Hashimoto, Ayato Hayashi, Satoshi Hirakawa, Atsuko Fujikawa, Yumiko Hori, Kentaro Matsuoka, Hideki Mori, Yuki Yamamoto, Shunsuke Yuzuriha, Naoaki Rikihisa, Shoji Watanabe, Shinichi Watanabe, Tatsuo Kuroda, Shunsuke Sugawara, Kosuke Ishikawa, Satoru Sasaki

    Japanese journal of radiology　38　(4)　287-342　2020/04

    DOI： 10.1007/s11604-019-00885-5 　

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    The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety, and systematizing treatment, employing evidence-based medicine (EBM) techniques and aimed at improvement of the outcomes. Clinical questions (CQs) were decided based on the important clinical issues. For document retrieval, key words for literature searches were set for each CQ and literature published from 1980 to the end of September 2014 was searched in Pubmed, Cochrane Library, and Japana Centra Revuo Medicina (JCRM). The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System (MINDS) technique. A total of 33 CQs were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy, and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

  64. Japanese clinical practice guidelines for vascular anomalies 2017. International-journal Peer-reviewed

    Hidefumi Mimura, Sadanori Akita, Akihiro Fujino, Masatoshi Jinnin, Mine Ozaki, Keigo Osuga, Hiroki Nakaoka, Eiichi Morii, Akira Kuramochi, Yoko Aoki, Yasunori Arai, Noriko Aramaki, Masanori Inoue, Yuki Iwashina, Tadashi Iwanaka, Shigeru Ueno, Akihiro Umezawa, Michio Ozeki, Junko Ochi, Yoshiaki Kinoshita, Masakazu Kurita, Shien Seike, Nobuyuki Takakura, Masataka Takahashi, Takao Tachibana, Kumiko Chuman, Shuji Nagata, Mitsunaga Narushima, Yasunari Niimi, Shunsuke Nosaka, Taiki Nozaki, Kazuki Hashimoto, Ayato Hayashi, Satoshi Hirakawa, Atsuko Fujikawa, Yumiko Hori, Kentaro Matsuoka, Hideki Mori, Yuki Yamamoto, Shunsuke Yuzuriha, Naoaki Rikihisa, Shoji Watanabe, Shinichi Watanabe, Tatsuo Kuroda, Shunsuke Sugawara, Kosuke Ishikawa, Satoru Sasaki

    Pediatrics international : official journal of the Japan Pediatric Society　62　(3)　257-304　2020/03

    DOI： 10.1111/ped.14077 　

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    The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety, and systematizing treatment, employing evidence-based medicine (EBM) techniques and aimed at improvement of the outcomes. Clinical questions (CQs) were decided based on the important clinical issues. For document retrieval, key words for literature searches were set for each CQ and literature published from 1980 to the end of September 2014 was searched in Pubmed, Cochrane Library, and Japana Centra Revuo Medicina (JCRM). The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System (MINDS) technique. A total of 33 CQs were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy, and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

  65. Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. International-journal Peer-reviewed

    Yoichi Wada, Atsuo Kikuchi, Akimune Kaga, Naoki Shimizu, Junya Ito, Ryo Onuma, Fumiyoshi Fujishima, Eriko Totsune, Ryo Sato, Tetsuya Niihori, Matsuyuki Shirota, Ryo Funayama, Kota Sato, Toru Nakazawa, Keiko Nakayama, Yoko Aoki, Setsuya Aiba, Kiyotaka Nakagawa, Shigeo Kure

    PLoS genetics　16　(2)　e1008628　2020/02/26

    DOI： 10.1371/journal.pgen.1008628 　

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    Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

  66. RRAS2の活性化変異はヌーナン症候群を引き起こす

    新堀 哲也, 永井 康貴, 大橋 博文, 岡本 伸彦, 岡田 賢, 木原 裕貴, 青木 洋子

    日本小児科学会雑誌　124　(2)　236-236　2020/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  67. がん遺伝子パネル検査の時代を迎えて 治療に直結した2例の報告

    新妻 秀剛, 片山 紗乙莉, 森谷 邦彦, 渡辺 祐子, 入江 正寛, 力石 健, 新堀 哲也, 青木 洋子, 末原 義之, 加藤 俊介, 笹原 洋二, 呉 繁夫

    日本小児科学会雑誌　124　(1)　99-99　2020/01

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  68. Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome. International-journal Peer-reviewed

    Sou Niitsuma, Hiroki Kudo, Atsuo Kikuchi, Takaya Hayashi, Satoshi Kumakura, Shuhei Kobayashi, Yuko Okuyama, Naonori Kumagai, Tetsuya Niihori, Yoko Aoki, Takanori So, Ryo Funayama, Keiko Nakayama, Matsuyuki Shirota, Shuji Kondo, Shoji Kagami, Hiroyasu Tsukaguchi, Kazumoto Iijima, Shigeo Kure, Naoto Ishii

    International immunology　2019/12/24

    DOI： 10.1093/intimm/dxz081 　

    ISSN： 0953-8178

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    Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1β, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1β. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1β for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.

  69. Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome. Peer-reviewed

    Yasuko Shoji, Shinobu Ida, Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto, Yuri Etani, Masanobu Kawai

    Endocrine journal　66　(11)　983-994　2019/11/28

    DOI： 10.1507/endocrj.EJ18-0564 　

    ISSN： 0918-8959

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    Noonan syndrome (NS) is a heterogeneous disorder with multiple congenital malformations. Recent advances in molecular and genetic approaches have identified a number of responsible genes for NS, most of which are components of the RAS/MAPK signaling pathway, and genotype-phenotype correlation analyses have been extensively performed; however, analysis of Japanese NS patients is limited. Here, we evaluated clinical characteristics in genetically diagnosed NS patients and their relationships to genotypes. A total of 48 clinically diagnosed NS were included, and responsible mutations were identified in 39 patients (81.3%) with PTPN11 mutations being the most prevalent followed by SOS1 mutations. Cardiac anomalies including pulmonary stenosis and hypertrophic cardiomyopathy were most prevalent (87.2%), and the prevalence of hypertrophic cardiomyopathy was greater in patients without PTPN11 mutations than in those with PTPN11 mutations. Short stature was the second-most prevalent (69.2%) characteristic, and present height SD score was significantly associated with height SD score at 1 year old. Patients with SOS1 mutations had greater present height SD score and better growth during infancy. These findings suggest the presence of a genotype-phenotype correlation in Japanese patients with NS, which enables us to use genetic information to predict the clinical course and may allow for genotype-based medical interventions.

  70. 日本人dysferlin遺伝子解析で見出されたバリアントの一般頻度による病的意義の推定

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　59　(Suppl.)　S257-S257　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  71. GALMの両アレル性変異はガラクトース血症IV型を呈する

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 岩澤 伸哉, 竹澤 祐介, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲哉, 小原 收, 青木 洋子, 深尾 敏幸, 呉 繁夫

    日本先天代謝異常学会雑誌　35　114-114　2019/09

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  72. Case of Noonan Syndrome With an Expanding Coronary Arterial Aneurysm. International-journal Peer-reviewed

    Ogihara Y, Fujimoto N, Ohashi H, Yamamoto N, Ito H, Mitani Y, Aoki Y, Imanaka-Yosida K, Ito M, Dohi K

    Circulation. Cardiovascular imaging　12　(9)　e009429　2019/09

    DOI： 10.1161/CIRCIMAGING.119.009429 　

    ISSN： 1941-9651

  73. 先天奇形症候群の前脳神経細胞特異的な病態モデル動物の作製

    森谷 晃, 井上 晋一, 青木 洋子, 大西 浩史

    The Kitakanto Medical Journal　69　(3)　299-299　2019/08

    Publisher: 北関東医学会

    ISSN： 1343-2826

    eISSN： 1881-1191

  74. LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases. International-journal Peer-reviewed

    Taiki Abe, Ikumi Umeki, Shin-Ichiro Kanno, Shin-Ichi Inoue, Tetsuya Niihori, Yoko Aoki

    Cell death and differentiation　27　(3)　1023-1035　2019/07/23

    DOI： 10.1038/s41418-019-0395-5 　

    ISSN： 1350-9047

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    Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. Mutations in LZTR1 have been identified in glioblastoma, schwannomatosis, and Noonan syndrome. However, the functional role of LZTR1 in carcinogenesis or human development is not fully understood. Here, we demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. The polyubiquitination and degradation of RAS was also observed in cells expressing MRAS, HRAS, NRAS, and KRAS as well as oncogenic RAS mutants and inhibited the activation of ERK1/2 and cell growth. In vivo ubiquitination assays showed that MRAS-K127 and HRAS-K170 were ubiquitinated by LZTR1 and that the polyubiquitinated-chains contained mainly Ub-K48, K63, and K33-linked chains, suggesting its possible involvement in autophagy. Immunoprecipitation analyses showed the interaction of LZTR1 and RAS-GTPases with autophagy-related proteins, including LC3B and SQSTM1/p62. Co-expression of LZTR1 and RAS increased the expression of lipidated form of LC3B. However, long-term treatment with chloroquine had little effect on RAS protein levels, suggesting that the contribution of autophagy to LZTR1-mediated RAS degradation is minimal. Taken together, these results show that LZTR1 functions as a "RAS killer protein" mainly via the ubiquitin-proteasome pathway regardless of the type of RAS GTPase, controlling downstream signal transduction. Our results also suggest a possible association of LZTR1 and RAS-GTPases with the autophagy. These findings provide clues for the elucidation of the mechanisms of RAS degradation and regulation of the RAS/MAPK signaling cascade.

  75. 幼少期に網膜血管腫から診断されたvon Hippel-Lindau病の1例

    津幡 真理, 永井 康貴, 堅田 有宇, 井上 彩, 新堀 哲也, 青木 洋子

    日本遺伝カウンセリング学会誌　40　(2)　149-149　2019/07

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  76. MAPK8IP3遺伝子のde novo病的バリアントは痙性両麻痺、脳構造異常を伴う知的発達障害の原因となる

    要 匡, 柳 久美子, 岩澤 伸哉, 菊池 敦生, 黒澤 健司, 松本 浩, 竹下 芽衣子, 小林 奈々, 川目 裕, 青木 洋子, 松本 直通, 東海林 亙, 呉 繁夫, 松原 洋一

    日本遺伝カウンセリング学会誌　40　(2)　91-91　2019/07

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  77. 大規模ゲノムコホート調査におけるBRCA1/2遺伝子の病的バリアント保持者への遺伝情報回付に関する課題

    濱中 洋平, 石田 孝宣, 布施 昇男, 川目 裕, 山口 由美, 安田 純, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 青木 洋子, 長神 風二, 八重樫 伸生, 木下 賢吾, 呉 繁夫, 山本 雅之

    日本乳癌学会総会プログラム抄録集　27回　332-332　2019/07

    Publisher: (一社)日本乳癌学会

  78. Germline-Activating RRAS2 Mutations Cause Noonan Syndrome. International-journal Peer-reviewed

    Tetsuya Niihori, Koki Nagai, Atsushi Fujita, Hirofumi Ohashi, Nobuhiko Okamoto, Satoshi Okada, Atsuko Harada, Hirotaka Kihara, Thomas Arbogast, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Taiki Abe, Shin-Ichi Inoue, I-Chun Tsai, Naomichi Matsumoto, Erica E Davis, Nicholas Katsanis, Yoko Aoki

    American journal of human genetics　104　(6)　1233-1240　2019/06/06

    DOI： 10.1016/j.ajhg.2019.04.014 　

    ISSN： 0002-9297

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    Noonan syndrome (NS) is characterized by distinctive craniofacial appearance, short stature, and congenital heart disease. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the RAS/mitogen-activating protein kinase (MAPK) pathway. However, the underlying genetic causes in nearly 20% of individuals with NS phenotype remain unexplained. Here, we report four de novo RRAS2 variants in three individuals with NS. RRAS2 is a member of the RAS subfamily and is ubiquitously expressed. Three variants, c.70_78dup (p.Gly24_Gly26dup), c.216A>T (p.Gln72His), and c.215A>T (p.Gln72Leu), have been found in cancers; our functional analyses showed that these three changes induced elevated association of RAF1 and that they activated ERK1/2 and ELK1. Notably, prominent activation of ERK1/2 and ELK1 by p.Gln72Leu associates with the severe phenotype of the individual harboring this change. To examine variant pathogenicity in vivo, we generated zebrafish models. Larvae overexpressing c.70_78dup (p.Gly24_Gly26dup) or c.216A>T (p.Gln72His) variants, but not wild-type RRAS2 RNAs, showed craniofacial defects and macrocephaly. The same dose injection of mRNA encoding c.215A>T (p.Gln72Leu) caused severe developmental impairments and low dose overexpression of this variant induced craniofacial defects. In contrast, the RRAS2 c.224T>G (p.Phe75Cys) change, located on the same allele with p.Gln72His in an individual with NS, resulted in no aberrant in vitro or in vivo phenotypes by itself. Together, our findings suggest that activating RRAS2 mutations can cause NS and expand the involvement of RRAS2 proto-oncogene to rare germline disorders.

  79. Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. International-journal Peer-reviewed

    Shinya Iwasawa, Kumiko Yanagi, Atsuo Kikuchi, Yasuko Kobayashi, Kazuhiro Haginoya, Hiroshi Matsumoto, Kenji Kurosawa, Masayuki Ochiai, Yasunari Sakai, Atsushi Fujita, Noriko Miyake, Tetsuya Niihori, Matsuyuki Shirota, Ryo Funayama, Shigeaki Nonoyama, Shouichi Ohga, Hiroshi Kawame, Keiko Nakayama, Yoko Aoki, Naomichi Matsumoto, Tadashi Kaname, Yoichi Matsubara, Wataru Shoji, Shigeo Kure

    Annals of neurology　85　(6)　927-933　2019/06

    DOI： 10.1002/ana.25481 　

    ISSN： 0364-5134

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    c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is an adaptor protein of the kinesin-1 complex and essential for axonal transport in neurons. However, an association between MAPK8IP3 variants and human disease has not been established. We identified 5 individuals from four families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Zebrafish embryos overexpressing human mutant JIP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons. Our results suggest that MAPK8IP3 variants cause a neurodevelopmental disease. ANN NEUROL 2019;85:927-933.

  80. Biallelic GALM pathogenic variants cause a novel type of galactosemia. International-journal Peer-reviewed

    Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

    Genetics in medicine : official journal of the American College of Medical Genetics　21　(6)　1286-1294　2019/06

    DOI： 10.1038/s41436-018-0340-x 　

    ISSN： 1098-3600

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    PURPOSE: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. METHODS: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. RESULTS: The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. CONCLUSION: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

  81. JIP3をコードするMAPK8IP3のrecurrent de novo variantsは痙性麻痺、知的障害、脳梁低形成を起こす

    菊池 敦生, 岩澤 伸哉, 柳 久美子, 小林 康子, 萩野谷 和裕, 松本 浩, 黒澤 健司, 落合 正行, 酒井 康成, 三宅 紀子, 松本 直通, 要 匡, 青木 洋子, 東海林 亙, 呉 繁夫

    脳と発達　51　(Suppl.)　S265-S265　2019/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  82. Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome. International-journal Peer-reviewed

    Sato Suzuki-Muromoto, Takuya Miyabayashi, Koki Nagai, Saeko Yamamura-Suzuki, Mai Anzai, Yusuke Takezawa, Ryo Sato, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Noriko Togashi, Atsuo Kikuchi, Tetsuya Niihori, Yoko Aoki, Shigeo Kure, Kazuhiro Haginoya

    Journal of human genetics　64　(5)　499-504　2019/05

    DOI： 10.1038/s10038-019-0579-3 　

    ISSN： 1434-5161

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    The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.

  83. 遺伝学的分析から特定された17患者中9名における病原性変異の候補(Genomic analysis identified candidate pathogenic variants in 9 of 17 patients)

    Takezawa Yusuke, Kikuchi Atsuo, Haginoya Kazuhiro, Niihari Tetsuya, Numata-Uematsu Yurika, Inui Takehiko, Yamamura-Suzuki Saeko, Miyabayashi Takuya, Anzai Mai, Suzuki-Muromoto Sato, Okubo Yukimune, Endo Wakaba, Togashi Noriko, Kobayashi Yasuko, Onuma Akira, Funayama Ryo, Shirota Matsuyuki, Nakayama Keiko, Aoki Yoko, Kure Shigeo

    日本小児科学会雑誌　123　(2)　292-292　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  84. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome. Peer-reviewed

    Inoue SI, Morozumi N, Yoshikiyo K, Maeda H, Aoki Y

    Human molecular genetics　28　(1)　74-83　2019/01

    DOI： 10.1093/hmg/ddy333 　

    ISSN： 0964-6906

  85. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. International-journal Peer-reviewed

    Ikumi Umeki, Tetsuya Niihori, Taiki Abe, Shin-Ichiro Kanno, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Keisuke Nagasaki, Makoto Yoshida, Hirofumi Ohashi, Shin-Ichi Inoue, Yoichi Matsubara, Ikuma Fujiwara, Shigeo Kure, Yoko Aoki

    Human genetics　138　(1)　21-35　2019/01

    DOI： 10.1007/s00439-018-1951-7 　

    ISSN： 0340-6717

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    RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1-PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1-PPP1CB complex as a component of the RAS/MAPK pathway.

  86. Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome. International-journal Peer-reviewed

    Yusuke Takezawa, Hiromi Fujie, Atsuo Kikuchi, Tetsuya Niihori, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Yoko Aoki, Masayuki Sasaki, Shigeo Kure

    Brain & development　40　(10)　934-938　2018/11

    DOI： 10.1016/j.braindev.2018.06.010 　

    ISSN： 0387-7604

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    BACKGROUND: IARS2 encodes isoleucine-tRNA synthetase, which is aclass-1 amino acyl-tRNA synthetase. IARS2 mutations are reported to cause Leigh syndrome or cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysphasia syndrome (CAGSSS). To our knowledge, IARS2 mutations and diseases related to it have only been reported in three families. Here we report a case of two Japanese siblings with Leigh syndrome, some features of CAGSSS, and West syndrome that are found to have compound heterozygous novel IARS2 mutations. CASE REPORT: A 7-month-old Japanese girl presented with infantile spasms. Brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy and hyperintensity in the bilateral basal ganglia. Three years later, her younger sister also presented with infantile spasms. MRI revealed diffuse brain atrophy and hyperintensity of the bilateral ganglia, suggesting Leigh syndrome. The siblings were identified with compound heterozygous missense mutations in IARS2, p.[(Phe227Ser)];[(Arg817His)]. CONCLUSION: This is the first case study reporting Leigh syndrome concomitant with some features of CAGSSS in siblings with novel IARS2 mutations, thereby broadening the phenotypic spectrum of IARS2-related disorders. Further studies are warranted to elucidate the nature of these disorders.

  87. Co-occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death. International-journal Peer-reviewed

    Akihiro Tamura, Suguru Uemura, Kousaku Matsubara, Eru Kozuki, Toshikatsu Tanaka, Nanako Nino, Takehito Yokoi, Atsuro Saito, Toshiaki Ishida, Daiichiro Hasegawa, Ikumi Umeki, Tetsuya Niihori, Yozo Nakazawa, Kenichi Koike, Yoko Aoki, Yoshiyuki Kosaka

    Clinical case reports　6　(7)　1202-1207　2018/07

    DOI： 10.1002/ccr3.1568 　

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    We report a case of a neonate with Noonan syndrome presenting with concurrent hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia, which resulted in premature death. Cases with Noonan syndrome diagnosed during the neonatal period might not necessarily show mild clinical course, and premature death is a possible outcome to be considered.

  88. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. International-journal Peer-reviewed

    Shazia Ashraf, Hiroki Kudo, Jia Rao, Atsuo Kikuchi, Eugen Widmeier, Jennifer A Lawson, Weizhen Tan, Tobias Hermle, Jillian K Warejko, Shirlee Shril, Merlin Airik, Tilman Jobst-Schwan, Svjetlana Lovric, Daniela A Braun, Heon Yung Gee, David Schapiro, Amar J Majmundar, Carolin E Sadowski, Werner L Pabst, Ankana Daga, Amelie T van der Ven, Johanna M Schmidt, Boon Chuan Low, Anjali Bansal Gupta, Brajendra K Tripathi, Jenny Wong, Kirk Campbell, Kay Metcalfe, Denny Schanze, Tetsuya Niihori, Hiroshi Kaito, Kandai Nozu, Hiroyasu Tsukaguchi, Ryojiro Tanaka, Kiyoshi Hamahira, Yasuko Kobayashi, Takumi Takizawa, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Naonori Kumagai, Kazumoto Iijima, Henry Fehrenbach, Jameela A Kari, Sherif El Desoky, Sawsan Jalalah, Radovan Bogdanovic, Nataša Stajić, Hildegard Zappel, Assel Rakhmetova, Sharon-Rose Wassmer, Therese Jungraithmayr, Juergen Strehlau, Aravind Selvin Kumar, Arvind Bagga, Neveen A Soliman, Shrikant M Mane, Lewis Kaufman, Douglas R Lowy, Mohamad A Jairajpuri, Richard P Lifton, York Pei, Martin Zenker, Shigeo Kure, Friedhelm Hildebrandt

    Nature communications　9　(1)　1960-1960　2018/05/17

    DOI： 10.1038/s41467-018-04193-w 　

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    No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.

  89. Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation. International-journal Peer-reviewed

    Haruhiko Nakamura, Mitsugu Uematsu, Yurika Numata-Uematsu, Yu Abe, Wakaba Endo, Atsuo Kikuchi, Yusuke Takezawa, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuya Niihori, Yoko Aoki, Kazuhiro Haginoya, Shigeo Kure

    Brain & development　40　(5)　410-414　2018/05

    DOI： 10.1016/j.braindev.2017.12.015 　

    ISSN： 0387-7604

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    Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature.

  90. Genomic analysis identifies masqueraders of full-term cerebral palsy. International-journal Peer-reviewed

    Yusuke Takezawa, Atsuo Kikuchi, Kazuhiro Haginoya, Tetsuya Niihori, Yurika Numata-Uematsu, Takehiko Inui, Saeko Yamamura-Suzuki, Takuya Miyabayashi, Mai Anzai, Sato Suzuki-Muromoto, Yukimune Okubo, Wakaba Endo, Noriko Togashi, Yasuko Kobayashi, Akira Onuma, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Yoko Aoki, Shigeo Kure

    Annals of clinical and translational neurology　5　(5)　538-551　2018/05

    DOI： 10.1002/acn3.551 　

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    Objective: Cerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full-term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders. Methods: A total of 107 patients-all full-term births-without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole-exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines. Results: Pathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1,CYP2U1,SPAST,GNAO1,CACNA1A,AMPD2,STXBP1, and SCN2A. Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice-site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments. Interpretation: The high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full-term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy.

  91. Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice. International-journal Peer-reviewed

    Shin-Ichi Inoue, Shingo Takahara, Takeo Yoshikawa, Tetsuya Niihori, Kazuhiko Yanai, Yoichi Matsubara, Yoko Aoki

    Human molecular genetics　26　(23)　4715-4727　2017/12/01

    DOI： 10.1093/hmg/ddx354 　

    ISSN： 0964-6906

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    Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.

  92. Patient with a novel purine-rich element binding protein A mutation. International-journal Peer-reviewed

    Nobuhiko Okamoto, Hideto Nakao, Tetsuya Niihori, Yoko Aoki

    Congenital anomalies　57　(6)　201-204　2017/11

    DOI： 10.1111/cga.12214 　

    ISSN： 0914-3505

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    There have been several reports on 5q31.3 microdeletion syndrome. The overlapping deleted region includes purine-rich element binding protein A (PURA), which encodes transcriptional activator protein Pur-α. Patients with PURA mutations show moderate to severe neurodevelopmental delay and learning disability. Neonatal hypotonia, respiratory insufficiency, feeding difficulties, and seizures are often seen. Dysmorphic features including myopathic faces are helpful as clinical signs of the diagnosis. We report a patient with a novel PURA mutation detected by whole-exome sequencing. We suggest that PURA abnormality is a recognizable syndrome.

  93. NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis Peer-reviewed

    Hidefumi Fukushima, Kouhei Shimizu, Asami Watahiki, Seira Hoshikawa, Tomoki Kosho, Daiju Oba, Seiji Sakano, Makiko Arakaki, Aya Yamada, Katsuyuki Nagashima, Koji Okabe, Satoshi Fukumoto, Eijiro Jimi, Anna Bigas, Keiichi I. Nakayama, Keiko Nakayama, Yoko Aoki, Wenyi Wei, Hiroyuki Inuzuka

    MOLECULAR CELL　68　(4)　645-+　2017/11

    DOI： 10.1016/j.molcel.2017.10.018 　

    ISSN： 1097-2765

    eISSN： 1097-4164

  94. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. International-journal Peer-reviewed

    Kimiko Ueda, Masako Yaoita, Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto

    American journal of medical genetics. Part A　173　(9)　2346-2352　2017/09

    DOI： 10.1002/ajmg.a.38337 　

    ISSN： 1552-4825

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    RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.

  95. Long-term outcome of a 26-year-old woman with West syndrome and an nuclear receptor subfamily 2 group F member 1 gene (NR2F1) mutation. International-journal Peer-reviewed

    Naomi Hino-Fukuyo, Atsuo Kikuchi, Hiroyuki Yokoyama, Kazuie Iinuma, Mieko Hirose, Kazuhiro Haginoya, Tetsuya Niihori, Keiko Nakayama, Yoko Aoki, Shigeo Kure

    Seizure　50　144-146　2017/08

    DOI： 10.1016/j.seizure.2017.06.018 　

    ISSN： 1059-1311

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    Long-term outcome of West syndrome with a NR2F1 mutation.

  96. Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties. International-journal Peer-reviewed

    Junpei Tanigawa, Haruka Mimatsu, Seiji Mizuno, Nobuhiko Okamoto, Daisuke Fukushi, Koji Tominaga, Hiroyuki Kidokoro, Yukako Muramatsu, Eriko Nishi, Shota Nakamura, Daisuke Motooka, Noriko Nomura, Kiyoshi Hayasaka, Tetsuya Niihori, Yoko Aoki, Shin Nabatame, Masahiro Hayakawa, Jun Natsume, Keiichi Ozono, Taroh Kinoshita, Nobuaki Wakamatsu, Yoshiko Murakami

    Human mutation　38　(7)　805-815　2017/07

    DOI： 10.1002/humu.23219 　

    ISSN： 1059-7794

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    Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.

  97. Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer. International-journal Peer-reviewed

    Naoki Tode, Toshiaki Kikuchi, Tomohiro Sakakibara, Taizou Hirano, Akira Inoue, Shinya Ohkouchi, Tsutomu Tamada, Tatsuma Okazaki, Akira Koarai, Hisatoshi Sugiura, Tetsuya Niihori, Yoko Aoki, Keiko Nakayama, Kunio Matsumoto, Yoichi Matsubara, Masayuki Yamamoto, Akira Watanabe, Toshihiro Nukiwa, Masakazu Ichinose

    Cancer science　108　(6)　1263-1270　2017/06

    DOI： 10.1111/cas.13233 　

    ISSN： 1347-9032

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    Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral-blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR-mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto-oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR-mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3-mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR-mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR-mutant lung cancer by underscoring MET-related signaling molecules.

  98. Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki

    Neurobiology of aging　53　194.e1-194.e8-194.e8　2017/05

    DOI： 10.1016/j.neurobiolaging.2017.01.004 　

    ISSN： 0197-4580

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in 1 patient. In addition, 18 patients harbored 1-3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTN variants were 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.

  99. Dramatic response after functional hemispherectomy in a patient with epileptic encephalopathy carrying a de novo COL4A1 mutation. International-journal Peer-reviewed

    Hino-Fukuyo N, Kikuchi A, Iwasaki M, Sato Y, Kubota Y, Kobayashi T, Nakayama T, Haginoya K, Arai-Ichinoi N, Niihori T, Sato R, Suzuki T, Kudo H, Funayama R, Nakayama K, Aoki Y, Kure S

    Brain & development　39　(4)　337-340　2017/04

    DOI： 10.1016/j.braindev.2016.11.006 　

    ISSN： 0387-7604

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    We describe the first case of a successful functional hemispherectomy in a patient with epileptic encephalopathy and a de novo collagen type IV alpha 1 (COL4A1) mutation. A 4-year-old girl was COL4A1 mutation-positive and suffered from drug-resistant epilepsy, hemiplegia, and developmental delay. Magnetic resonance imaging detected no porencephaly, and she had no cataract or renal abnormality. Following a presurgical evaluation for epilepsy, she underwent a functional hemispherectomy. She has been seizure free with no intracranial hemorrhage or other perioperative complications. Patients with a COL4A1 mutation have an increased risk for intracranial hemorrhage because of disrupted integrity in the vascular basement membrane due to the mutation. After weighing the risks and benefits to these patients, epilepsy surgery may not be absolutely contraindicated. Furthermore, pediatric neurologists should be aware of an undiagnosed COL4A1 mutation when a patient presents with an unexplained neurological phenotype, such as mild hemiparesis, even in the absence of porencephaly.

  100. Prominent sensory involvement in a case of familial amyotrophic lateral sclerosis carrying the L8V SOD1 mutation. International-journal Peer-reviewed

    Ayumi Nishiyama, Hitoshi Warita, Toshiaki Takahashi, Naoki Suzuki, Shuhei Nishiyama, Ohito Tano, Tetsuya Akiyama, Yasuaki Watanabe, Kenta Takahashi, Hiroshi Kuroda, Masaaki Kato, Maki Tateyama, Tetsuya Niihori, Yoko Aoki, Masashi Aoki

    Clinical neurology and neurosurgery　150　194-196　2016/11

    DOI： 10.1016/j.clineuro.2016.08.008 　

    ISSN： 0303-8467

  101. Variants in the UBR1 gene are not associated with chronic pancreatitis in Japan Peer-reviewed

    Atsushi Masamune, Eriko Nakano, Tetsuya Niihori, Shin Hamada, Masao Nagasaki, Yoko Aoki, Tooru Shimosegawa

    PANCREATOLOGY　16　(5)　814-818　2016/09

    DOI： 10.1016/j.pan.2016.06.662 　

    ISSN： 1424-3903

    eISSN： 1424-3911

  102. Human genetic variation database, a reference database of genetic variations in the Japanese population. International-journal Peer-reviewed

    Koichiro Higasa, Noriko Miyake, Jun Yoshimura, Kohji Okamura, Tetsuya Niihori, Hirotomo Saitsu, Koichiro Doi, Masakazu Shimizu, Kazuhiko Nakabayashi, Yoko Aoki, Yoshinori Tsurusaki, Shinichi Morishita, Takahisa Kawaguchi, Osuke Migita, Keiko Nakayama, Mitsuko Nakashima, Jun Mitsui, Maiko Narahara, Keiko Hayashi, Ryo Funayama, Daisuke Yamaguchi, Hiroyuki Ishiura, Wen-Ya Ko, Kenichiro Hata, Takeshi Nagashima, Ryo Yamada, Yoichi Matsubara, Akihiro Umezawa, Shoji Tsuji, Naomichi Matsumoto, Fumihiko Matsuda

    Journal of human genetics　61　(6)　547-53　2016/06

    DOI： 10.1038/jhg.2016.12 　

    ISSN： 1434-5161

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    Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/.

  103. ヌーナン症候群の遺伝カウンセリング

    川戸 和美, 松田 圭子, 三島 祐子, 山本 悠斗, 新堀 哲也, 青木 洋子, 岡本 伸彦

    日本遺伝カウンセリング学会誌　37　(1)　87-87　2016/03

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  104. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. International-journal Peer-reviewed

    Masako Yaoita, Tetsuya Niihori, Seiji Mizuno, Nobuhiko Okamoto, Shion Hayashi, Atsushi Watanabe, Masato Yokozawa, Hiroshi Suzumura, Akihiko Nakahara, Yusuke Nakano, Tatsunori Hokosaki, Ayumi Ohmori, Hirofumi Sawada, Ohsuke Migita, Aya Mima, Pablo Lapunzina, Fernando Santos-Simarro, Sixto García-Miñaúr, Tsutomu Ogata, Hiroshi Kawame, Kenji Kurosawa, Hirofumi Ohashi, Shin-Ichi Inoue, Yoichi Matsubara, Shigeo Kure, Yoko Aoki

    Human genetics　135　(2)　209-22　2016/02

    DOI： 10.1007/s00439-015-1627-5 　

    ISSN： 0340-6717

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    RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.

  105. Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities. International-journal Peer-reviewed

    Yuko Watanabe, Kosuke Shido, Tetsuya Niihori, Hidetaka Niizuma, Yu Katata, Chie Iizuka, Daiju Oba, Kunihiko Moriya, Yuka Saito-Nanjo, Masaei Onuma, Takeshi Rikiishi, Yoji Sasahara, Mika Watanabe, Setsuya Aiba, Ryuta Saito, Yukihiko Sonoda, Teiji Tominaga, Yoko Aoki, Shigeo Kure

    American journal of medical genetics. Part A　170A　(1)　189-94　2016/01

    DOI： 10.1002/ajmg.a.37376 　

    ISSN： 1552-4825

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    Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets.

  106. Metachondromatosis without enchondromas Peer-reviewed

    Kohei Kanaya, Aki Ishikawa, Masako Yaoita, Tetsuya Niihori, Yoko Aoki, Kousuke Iba, Toshihiko Yamashita

    JBJS Case Connector　6　(2)　e30　2016

    Publisher: Lippincott Williams and Wilkins

    DOI： 10.2106/JBJS.CC.15.00182 　

    ISSN： 2160-3251

  107. Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype. International-journal Peer-reviewed

    Mitsuji Moriya, Shin-Ichi Inoue, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Daiju Oba, Tetsuya Niihori, Misato Hashi, Hiroshi Ohnishi, Shigeo Kure, Yoichi Matsubara, Yoko Aoki

    Human molecular genetics　24　(25)　7349-60　2015/12/20

    DOI： 10.1093/hmg/ddv435 　

    ISSN： 0964-6906

  108. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. International-journal Peer-reviewed

    Tetsuya Niihori, Meri Ouchi-Uchiyama, Yoji Sasahara, Takashi Kaneko, Yoshiko Hashii, Masahiro Irie, Atsushi Sato, Yuka Saito-Nanjo, Ryo Funayama, Takeshi Nagashima, Shin-Ichi Inoue, Keiko Nakayama, Keiichi Ozono, Shigeo Kure, Yoichi Matsubara, Masue Imaizumi, Yoko Aoki

    American journal of human genetics　97　(6)　848-54　2015/12/03

    DOI： 10.1016/j.ajhg.2015.10.010 　

    ISSN： 0002-9297

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    Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by thrombocytopenia and congenital fusion of the radius and ulna. A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause of RUSAT. However, HOXA11 mutations are absent in a number of individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT. In the current study, we performed whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation in MECOM, encoding EVI1, in the individual with RUSAT. Subsequent analysis of MECOM in two other individuals with RUSAT revealed two additional missense mutations. These three mutations were clustered within the 8(th) zinc finger motif of the C-terminal zinc finger domain of EVI1. Chromatin immunoprecipitation and qPCR assays of the regions harboring the ETS-like motif that is known as an EVI1 binding site showed a reduction in immunoprecipitated DNA for two EVI1 mutants compared with wild-type EVI1. Furthermore, reporter assays showed that MECOM mutations led to alterations in both AP-1- and TGF-β-mediated transcriptional responses. These functional assays suggest that transcriptional dysregulation by mutant EVI1 could be associated with the development of RUSAT. We report missense mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in normal hematopoiesis and in the development of forelimbs and fingers in humans.

  109. Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Toshiaki Takahashi, Naoki Suzuki, Maki Tateyama, Chigusa Watanabe, Kazuma Sugie, Hirotaka Nakanishi, Gen Sobue, Masaaki Kato, Hitoshi Warita, Yoko Aoki, Masashi Aoki

    Neurology. Genetics　1　(4)　e36　2015/12

    DOI： 10.1212/NXG.0000000000000036 　

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    OBJECTIVE: To investigate the genetic causes of suspected dysferlinopathy and to reveal the genetic profile for myopathies with dysferlin deficiency. METHODS: Using next-generation sequencing, we analyzed 42 myopathy-associated genes, including DYSF, in 64 patients who were clinically or pathologically suspected of having dysferlinopathy. Putative pathogenic mutations were confirmed by Sanger sequencing. In addition, copy-number variations in DYSF were investigated using multiplex ligation-dependent probe amplification. We also analyzed the genetic profile for 90 patients with myopathy with dysferlin deficiency, as indicated by muscle specimen immunohistochemistry, including patients from a previous cohort. RESULTS: We identified putative pathogenic mutations in 38 patients (59% of all investigated patients). Twenty-three patients had DYSF mutations, including 6 novel mutations. The remaining 16 patients, including a single patient who also carried the DYSF mutation, harbored putative pathogenic mutations in other genes. The genetic profile for 90 patients with dysferlin deficiency revealed that 70% had DYSF mutations (n = 63), 10% had CAPN3 mutations (n = 9), 2% had CAV3 mutations (n = 2), 3% had mutations in other genes (in single patients), and 16% did not have any identified mutations (n = 14). CONCLUSIONS: This study clarified the heterogeneous genetic profile for myopathies with dysferlin deficiency. Our results demonstrate the importance of a comprehensive analysis of related genes in improving the genetic diagnosis of dysferlinopathy as one of the most common subtypes of limb-girdle muscular dystrophy. Unresolved diagnoses should be investigated using whole-genome or whole-exome sequencing.

  110. Variants in pancreatic carboxypeptidase genes CPA2 and CPB1 are not associated with chronic pancreatitis. International-journal Peer-reviewed

    Eriko Nakano, Andrea Geisz, Atsushi Masamune, Tetsuya Niihori, Shin Hamada, Kiyoshi Kume, Yoichi Kakuta, Yoko Aoki, Yoichi Matsubara, Karolin Ebert, Maren Ludwig, Markus Braun, David A Groneberg, Tooru Shimosegawa, Miklós Sahin-Tóth, Heiko Witt

    American journal of physiology. Gastrointestinal and liver physiology　309　(8)　G688-94-94　2015/10/15

    DOI： 10.1152/ajpgi.00241.2015 　

    ISSN： 0193-1857

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    Genetic alterations in the carboxypeptidase A1 gene (CPA1) are associated with early onset chronic pancreatitis (CP). Besides CPA1, there are two other human pancreatic carboxypeptidases (CPA2 and CPB1). Here we examined whether CPA2 and CPB1 alterations are associated with CP in Japan and Germany. All exons and flanking introns of CPA2 and CPB1 were sequenced in 477 Japanese patients with CP (234 alcoholic, 243 nonalcoholic) and in 497 German patients with nonalcoholic CP by targeted next-generation sequencing and/or Sanger sequencing. Secretion and enzymatic activity of CPA2 and CPB1 variants were determined after transfection into HEK 293T cells. We identified six nonsynonymous CPA2 variants (p.V67I, p.G166R, p.D168E, p.D173H, p.R237W, and p.G388S), eight nonsynonymous CPB1 alterations (p.S65G, p.N120S, p.D172E, p.R195H, p.D208N, p.F232L, p.A317V, and p.D364Y), and one splice-site variant (c.687+1G>T) in CPB1. Functional analysis revealed essentially complete loss of function in CPA2 variants p.R237W and p.G388S and CPB1 variants p.R110H and p.D364Y. None of the CPA2 or CPB1 variants, including those resulting in a marked loss of function, were overrepresented in patients with CP. In conclusion, CPA2 and CPB1 variants are not associated with CP.

  111. Improved growth velocity of a patient with Noonan-like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low-dose growth hormone therapy Peer-reviewed

    Kei Takasawa, Shigeru Takishima, Chikako Morioka, Masato Nishioka, Hirofumi Ohashi, Yoko Aoki, Masayuki Shimohira, Kenichi Kashimada, Tomohiro Morio

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　167　(10)　2425-2429　2015/10

    DOI： 10.1002/ajmg.a.37191 　

    ISSN： 1552-4825

    eISSN： 1552-4833

  112. Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation. International-journal Peer-reviewed

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Toshiaki Takahashi, Maki Tateyama, Naoki Suzuki, Ayumi Nishiyama, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Satomi Mitsuhashi, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    Neurology. Genetics　1　(3)　e23　2015/10

    DOI： 10.1212/NXG.0000000000000023 　

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    OBJECTIVE: To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families. METHODS: Genetic investigations were performed using whole-exome and Sanger sequencing of the heterogeneous nuclear ribonucleoprotein A1 gene (hnRNPA1). The clinical and pathologic features of patients in the 2 families were evaluated with neurologic examinations, muscle imaging, and muscle biopsy. RESULTS: We identified a missense p.D314N mutation in hnRNPA1, which is also known to cause familial amyotrophic lateral sclerosis, in 2 families with IBM. The affected individuals developed muscle weakness in their 40s, which slowly progressed toward a limb-girdle pattern. Further evaluation of the affected individuals revealed no apparent motor neuron dysfunction, cognitive impairment, or bone abnormality. The muscle pathology was compatible with IBM, lacking apparent neurogenic change and inflammation. Multiple immunohistochemical analyses revealed the cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes and myonuclei. Furthermore, the aberrant accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-containing protein/p97, and a variety of RNA-binding proteins (RBPs). CONCLUSIONS: The present study expands the clinical phenotype of hnRNPA1-linked multisystem proteinopathy. Mutations in hnRNPA1, and possibly hnRNPA2B1, will be responsible for isolated IBM with a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remain to be elucidated, the immunohistochemical results suggest a broad sequestration of RBPs by the mutated hnRNPA1.

  113. A postzygotic NRAS mutation in a patient with Schimmelpenning syndrome. International-journal Peer-reviewed

    Yukiko Kuroda, Ikuko Ohashi, Yumi Enomoto, Takuya Naruto, Naoko Baba, Yukichi Tanaka, Noriko Aida, Nobuhiko Okamoto, Tetsuya Niihori, Yoko Aoki, Kenji Kurosawa

    American journal of medical genetics. Part A　167A　(9)　2223-5　2015/09

    DOI： 10.1002/ajmg.a.37135 　

    ISSN： 1552-4825

  114. Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome. International-journal Peer-reviewed

    Naomi Hino-Fukuyo, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Tetsuya Niihori, Ryo Sato, Tasuku Suzuki, Hiroki Kudo, Yuko Sato, Tojo Nakayama, Yosuke Kakisaka, Yuki Kubota, Tomoko Kobayashi, Ryo Funayama, Keiko Nakayama, Mitsugu Uematsu, Yoko Aoki, Kazuhiro Haginoya, Shigeo Kure

    Human genetics　134　(6)　649-58　2015/06

    DOI： 10.1007/s00439-015-1553-6 　

    ISSN： 0340-6717

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    West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

  115. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. International-journal Peer-reviewed

    Eriko Nakano, Atsushi Masamune, Tetsuya Niihori, Kiyoshi Kume, Shin Hamada, Yoko Aoki, Yoichi Matsubara, Tooru Shimosegawa

    Digestive diseases and sciences　60　(5)　1297-307　2015/05

    DOI： 10.1007/s10620-014-3476-9 　

    ISSN： 0163-2116

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    BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the development of cystic fibrosis, is known as a pancreatitis susceptibility gene. Direct DNA sequencing of PCR-amplified CFTR gene segments is a first-line method to detect unknown mutations, but it is a tedious and labor-intensive endeavor given the large size of the gene (27 exons, 1,480 amino acids). Next-generation sequencing (NGS) is becoming standardized, reducing the cost of DNA sequencing, and enabling the generation of millions of reads per run. We here report a comprehensive analysis of CFTR variants in Japanese patients with chronic pancreatitis using NGS coupling with target capture. METHODS: Exon sequences of the CFTR gene from 193 patients with chronic pancreatitis (121 idiopathic, 46 alcoholic, 17 hereditary, and nine familial) were captured by HaloPlex target enrichment technology, followed by NGS. RESULTS: The sequencing data covered 91.6 % of the coding regions of the CFTR gene by ≥ 20 reads with a mean read depth of 449. We could identify 12 non-synonymous variants including three novel ones [c.A1231G (p.K411E), c.1753G>T (p.E585X) and c.2869delC (p.L957fs)] and seven synonymous variants including three novel ones in the exonic regions. The frequencies of the c.4056G>C (p.Q1352H) and the c.3468G>T (p.L1156F) variants were higher in patients with chronic pancreatitis than those in controls. CONCLUSIONS: Target sequence capture combined with NGS is an effective method for the analysis of pancreatitis susceptibility genes.

  116. Mutations in PIGL in a patient with Mabry syndrome. International-journal Peer-reviewed

    Ikuma Fujiwara, Yoshiko Murakami, Tetsuya Niihori, Junko Kanno, Akiko Hakoda, Osamu Sakamoto, Nobuhiko Okamoto, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Taroh Kinoshita, Shigeo Kure, Yoichi Matsubara, Yoko Aoki

    American journal of medical genetics. Part A　167A　(4)　777-85　2015/04

    DOI： 10.1002/ajmg.a.36987 　

    ISSN： 1552-4825

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    Mabry syndrome, hyperphosphatasia mental retardation syndrome (HPMRS), is an autosomal recessive disease characterized by increased serum levels of alkaline phosphatase (ALP), severe developmental delay, intellectual disability, and seizures. Recent studies have revealed mutations in PIGV, PIGW, PIGO, PGAP2, and PGAP3 (genes that encode molecules of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway) in patients with HPMRS. We performed whole-exome sequencing of a patient with severe intellectual disability, distinctive facial appearance, fragile nails, and persistent increased serum levels of ALP. The result revealed a compound heterozygote with a 13-bp deletion in exon 1 (c.36_48del) and a two-base deletion in exon 2 (c.254_255del) in phosphatidylinositol glycan anchor, class L (PIGL) that caused frameshifts resulting in premature terminations. The 13-bp deletion was inherited from the father, and the two-base deletion was inherited from the mother. Expressing c.36_48del or c.254_255del cDNA with an HA-tag at the C- or N-terminus in PIGL-deficient CHO cells only partially restored the surface expression of GPI-anchored proteins (GPI-APs). Nonsynonymous changes or frameshift mutations in PIGL have been identified in patients with CHIME syndrome, a rare autosomal recessive disorder characterized by colobomas, congenital heart defects, early onset migratory ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Our patient did not have colobomas, congenital heart defects, or early onset migratory ichthyosiform dermatosis and hence was diagnosed with HPMRS, and not CHIME syndrome. These results suggest that frameshift mutations that result in premature termination in PIGL cause a phenotype that is consistent with HPMRS.

  117. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. International-journal Peer-reviewed

    Eriko Nishi, Seiji Mizuno, Yuka Nanjo, Tetsuya Niihori, Yoshimitsu Fukushima, Yoichi Matsubara, Yoko Aoki, Tomoki Kosho

    American journal of medical genetics. Part A　167A　(2)　407-11　2015/02

    DOI： 10.1002/ajmg.a.36842 　

    ISSN： 1552-4825

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    Noonan syndrome with multiple lentigines (NSML), formerly referred to as LEOPARD syndrome, is a rare autosomal-dominant condition, characterized by multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. To date, PTPN11, RAF1, and BRAF have been reported to be causal for NSML. We report on a 13-year-old Japanese boy, who was diagnosed with NSML. He was found to have a novel heterozygous missense variant (c.305A > G; p.E102G) in MAP2K1, a gene mostly causal for cardio-facio-cutaneous syndrome (CFCS). He manifested fetal macrosomia, and showed hypotonia and poor sucking in the neonatal period. He had mild developmental delay, and multiple lentigines appearing at approximately age 3 years, as well as flexion deformity of knees bilaterally, subtle facial characteristics including ocular hypertelorism, sensorineural hearing loss, and precocious puberty. He lacked congenital heart defects or hypertrophic cardiomyopathy, frequently observed in patients with NSML, mostly caused by PTPN11 mutations. He also lacked congenital heart defects, characteristic facial features, or intellectual disability, frequently observed in those with CFCS caused by MAP2K1 or MAP2K2 mutations. This may be the first patient clinically diagnosed with NSML, caused by a mutation in MAP2K1.

  118. Cardiofaciocutaneous syndrome, a Noonan syndrome related disorder: Clinical and molecular findings in 11 patients Peer-reviewed

    Atilano Carcavilla, Sixto Garcia-Minaur, Antonio Perez-Aytes, Teresa Vendrell, Isabel Pinto, Encarna Guillen-Navarro, Antonio Gonzalez-Meneses, Yoko Aoki, Daniel Grinberg, Begona Ezquieta

    MEDICINA CLINICA　144　(2)　67-72　2015/01

    DOI： 10.1016/j.medcli.2014.06.009 　

    ISSN： 0025-7753

    eISSN： 1578-8989

  119. New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. International-journal Peer-reviewed

    Shin-Ichi Inoue, Mitsuji Moriya, Yusuke Watanabe, Sachiko Miyagawa-Tomita, Tetsuya Niihori, Daiju Oba, Masao Ono, Shigeo Kure, Toshihiko Ogura, Yoichi Matsubara, Yoko Aoki

    Human molecular genetics　23　(24)　6553-66　2014/12/15

    DOI： 10.1093/hmg/ddu376 　

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    Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knockin mice (here Braf(Q241R/+)) expressing the Braf Q241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf(Q241R/+) mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf(Q241R/+) embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knockin mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf(Q241R/+) embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new Braf knockin mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome.

  120. GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Naoki Suzuki, Yoji Sasahara, Takeshi Rikiishi, Ayumi Nishiyama, Shuhei Nishiyama, Kaoru Endo, Masaaki Kato, Hitoshi Warita, Hidehiko Konno, Toshiaki Takahashi, Maki Tateyama, Takeshi Nagashima, Ryo Funayama, Keiko Nakayama, Shigeo Kure, Yoichi Matsubara, Yoko Aoki, Masashi Aoki

    Neuromuscular disorders : NMD　24　(12)　1068-72　2014/12

    DOI： 10.1016/j.nmd.2014.07.008 　

    ISSN： 0960-8966

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    GNE myopathy is an autosomal recessive muscular disorder caused by mutations in the gene encoding the key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we report two siblings with myopathy with rimmed vacuoles and congenital thrombocytopenia who harbored two compound heterozygous GNE mutations, p.V603L and p.G739S. Thrombocytopenia, which is characterized by shortened platelet lifetime rather than ineffective thrombopoiesis, has been observed since infancy. We performed exome sequencing and array CGH to identify the underlying genetic etiology of thrombocytopenia. No pathogenic variants were detected among the known causative genes of recessively inherited thrombocytopenia; yet, candidate variants in two genes that followed an autosomal recessive mode of inheritance, including previously identified GNE mutations, were detected. Alternatively, it is possible that the decreased activity of GNE/MNK itself, which would lead to decreased sialic content in platelets, is associated with thrombocytopenia in these patients. Further investigations are required to clarify the association between GNE myopathy and the pathogenesis of thrombocytopenia.

  121. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis Peer-reviewed

    Elisabetta Flex, Mamta Jaiswal, Francesca Pantaleoni, Simone Martinelli, Marion Strullu, Eyad K. Fansa, Aurelie Caye, Alessandro De Luca, Francesca Lepri, Radovan Dvorsky, Luca Pannone, Stefano Paolacci, Si-Cai Zhang, Valentina Fodale, Gianfranco Bocchinfuso, Cesare Rossi, Emma M. M. Burkitt-Wright, Andrea Farrotti, Emilia Stellacci, Serena Cecchetti, Rosangela Ferese, Lisabianca Bottero, Silvana Castro, Odile Fenneteau, Benoit Brethon, Massimo Sanchez, Amy E. Roberts, Helger G. Yntema, Ineke Van der Burgt, Paola Cianci, Marie-Louise Bondeson, Maria Cristina Digilio, Giuseppe Zampino, Bronwyn Kerr, Yoko Aoki, Mignon L. Loh, Antonio Palleschi, Elia Di Schiavi, Alessandra Care, Angelo Selicorni, Bruno Dallapiccola, Ion C. Cirstea, Lorenzo Stella, Martin Zenker, Bruce D. Gelb, Helene Cave, Mohammad R. Ahmadian, Marco Tartaglia

    HUMAN MOLECULAR GENETICS　23　(16)　4315-4327　2014/08

    DOI： 10.1093/hmg/ddu148 　

    ISSN： 0964-6906

    eISSN： 1460-2083

  122. Seven Novel Mutations in Bulgarian Patients with Acute Hepatic Porphyrias (AHP). Peer-reviewed

    Dragneva, Sonya Szyszka-Niagolov, Monika Ivanova, Aneta Mateva, Lyudmila Izumi, Rumiko Aoki, Yoko Matsubara, Yoichi

    JIMD Rep　2014/07/06

    DOI： 10.1007/8904_2014_320 　

  123. Sequential analysis of amino acid substitutions with hepatitis B virus in association with nucleoside/nucleotide analog treatment detected by deep sequencing. International-journal Peer-reviewed

    Masashi Ninomiya, Yasuteru Kondo, Tetsuya Niihori, Takeshi Nagashima, Takayuki Kogure, Eiji Kakazu, Osamu Kimura, Yoko Aoki, Yoichi Matsubara, Tooru Shimosegawa

    Hepatology research : the official journal of the Japan Society of Hepatology　44　(6)　678-84　2014/06

    DOI： 10.1111/hepr.12168 　

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    Taking nucleoside/nucleotide analogs is a major antiviral therapy for chronic hepatitis B infection. The problem with this treatment is the selection for drug-resistant mutants. Currently, identification of genotypic drug resistance is conducted by molecular cloning sequenced by the Sanger method. However, this methodology is complicated and time-consuming. These limitations can be overcome by deep sequencing technology. Therefore, we performed sequential analysis of the frequency of drug resistance in one individual, who was treated with lamivudine on-and-off therapy for 2 years, by deep sequencing. The lamivudine-resistant mutations at rtL180M and rtM204V and the entecavir-resistant mutation at rtT184L were detected in the first subject. The lamivudine- and entecavir-resistant strain was still detected in the last subject. However, in the deep sequencing analysis, rt180 of the first subject showed a mixture in 76.9% of the methionine and in 23.1% of the leucine, and rt204 also showed a mixture in 69.0% of the valine and 29.8% of the isoleucine. During the treatment, the ratio of resistant mutations increased. At rt184, the resistant variants were detectable in 58.7% of the sequence, with the replacement of leucine by the wild-type threonine in the first subject. Gradually, entecavir-resistant variants increased in 82.3% of the leucine in the last subject. In conclusion, we demonstrated the amino acid substitutions of the serial nucleoside/nucleotide analog resistants. We revealed that drug-resistant mutants appear unchanged at first glance, but actually there are low-abundant mutations that may develop drug resistance against nucleoside/nucleotide analogs through the selection of dominant mutations.

  124. Identification of a Novel Missense Mutation of MAF in a Japanese Family With Congenital Cataract by Whole Exome Sequencing: A Clinical Report and Review of Literature Peer-reviewed

    Yoko Narumi, Sachiko Nishina, Motoharu Tokimitsu, Yoko Aoki, Rika Kosaki, Keiko Wakui, Noriyuki Azuma, Toshinori Murata, Fumio Takada, Yoshimitsu Fukushima, Tomoki Kosho

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　164　(5)　1272-1276　2014/05

    DOI： 10.1002/ajmg.a.36433 　

    ISSN： 1552-4825

    eISSN： 1552-4833

  125. Bilateral giant coronary aneurysms in a 40-year-old male with Noonan syndrome caused by a KRAS germline mutation Peer-reviewed

    Naoki Fujimoto, Hiroshi Nakajima, Emiyo Sugiura, Kaoru Dohi, Shinji Kanemitsu, Norikazu Yamada, Yoko Aoki, Kaname Nakatani, Hideto Shimpo, Tsutomu Nobori, Masaaki Ito

    INTERNATIONAL JOURNAL OF CARDIOLOGY　173　(3)　E63-E66　2014/05

    DOI： 10.1016/j.ijcard.2014.03.135 　

    ISSN： 0167-5273

    eISSN： 1874-1754

  126. Acute Lymphoblastic Leukemia Developing in a Patient With Noonan Syndrome Harboring a PTPN11 Germline Mutation Peer-reviewed

    Kenichi Sakamoto, Toshihiko Imamura, Daisuke Asai, Sachiko Goto-Kawashima, Hideki Yoshida, Atsushi Fujiki, Akiyo Furutani, Hiroyuki Ishida, Yoko Aoki, Hajime Hosoi

    JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY　36　(2)　E136-E139　2014/03

    DOI： 10.1097/MPH.0000000000000002 　

    ISSN： 1077-4114

    eISSN： 1536-3678

  127. A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy. International-journal Peer-reviewed

    Keisuke Wakusawa, Satoru Kobayashi, Yu Abe, Soichiro Tanaka, Wakaba Endo, Takehiko Inui, Mitsutosi Iwaki, Shuei Watanabe, Noriko Togashi, Takahiro Nara, Tetsuya Niihori, Yoko Aoki, Kazuhiro Haginoya

    Brain & development　36　(1)　61-3　2014/01

    DOI： 10.1016/j.braindev.2012.12.007 　

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    We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy.

  128. TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia. International-journal Peer-reviewed

    Tsutomu Ogata, Tetsuya Niihori, Noriko Tanaka, Masahiko Kawai, Takeshi Nagashima, Ryo Funayama, Keiko Nakayama, Shinichi Nakashima, Fumiko Kato, Maki Fukami, Yoko Aoki, Yoichi Matsubara

    PloS one　9　(3)　e91598-e91598　2014

    DOI： 10.1371/journal.pone.0091598 　

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    BACKGROUND: Although TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS)-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We studied three subjects with craniofacial features and hypocalcemia (group 1), two subjects with craniofacial features alone (group 2), and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459) specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain. CONCLUSIONS/SIGNIFICANCE: Clinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes.

  129. A Transient Myelodysplastic/Myeloproliferative Neoplasm in a Patient With Cardio-Facio-Cutaneous Syndrome and a Germline BRAF Mutation Peer-reviewed

    Kazuhito Sekiguchi, Tomoki Maeda, So-ichi Suenobu, Nobutaka Kunisaki, Miki Shimizu, Kyoko Kiyota, Yo-suke Handa, Kensuke Akiyoshi, Seigo Korematsu, Yoko Aoki, Yoichi Matsubara, Tatsuro Izumi

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　161　(10)　2600-2603　2013/10

    DOI： 10.1002/ajmg.a.36107 　

    ISSN： 1552-4825

    eISSN： 1552-4833

  130. Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Yoko Aoki, Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Maki Tateyama, Takeshi Nagashima, Ryo Funayama, Koji Abe, Keiko Nakayama, Masashi Aoki, Yoichi Matsubara

    Journal of human genetics　58　(5)　259-66　2013/05

    DOI： 10.1038/jhg.2013.9 　

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    Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c.90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.

  131. Ras/MAPK syndromes and childhood hemato-oncological diseases Invited Peer-reviewed

    Yoko Aoki, Yoichi Matsubara

    International Journal of Hematology　97　(1)　30-36　2013/01

    DOI： 10.1007/s12185-012-1239-y 　

    ISSN： 0925-5710 1865-3774

  132. A case of almost unilateral focal dermal hypoplasia resulting from a novel mutation in the PORCN gene Peer-reviewed

    Masayuki Asano, Taku Fujimura, Chihiro Wakusawa, Yoko Aoki, Yoichi Matsubara, Setsuya Aiba

    Acta Dermato-Venereologica　93　(1)　120-121　2013

    DOI： 10.2340/00015555-1399 　

    ISSN： 0001-5555 1651-2057

  133. Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia. International-journal Peer-reviewed

    Yuka Saito, Yoko Aoki, Hideki Muramatsu, Hideki Makishima, Jaroslaw P Maciejewski, Masue Imaizumi, Takeshi Rikiishi, Yoji Sasahara, Shigeo Kure, Tetsuya Niihori, Shigeru Tsuchiya, Seiji Kojima, Yoichi Matsubara

    Leukemia research　36　(8)　1009-15　2012/08

    DOI： 10.1016/j.leukres.2012.04.018 　

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    Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL.

  134. Development of a Multi-Step Leukemogenesis Model of MLL-Rearranged Leukemia Using Humanized Mice Peer-reviewed

    Kunihiko Moriya, Makiko Suzuki, Yohei Watanabe, Takeshi Takahashi, Yoko Aoki, Toru Uchiyama, Satoru Kumaki, Yoji Sasahara, Masayoshi Minegishi, Shigeo Kure, Shigeru Tsuchiya, Kazuo Sugamura, Naoto Ishii

    PLOS ONE　7　(6)　e37892-e37892　2012/06

    DOI： 10.1371/journal.pone.0037892 　

    ISSN： 1932-6203

  135. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. International-journal Peer-reviewed

    Yu Abe, Yoko Aoki, Shinichi Kuriyama, Hiroshi Kawame, Nobuhiko Okamoto, Kenji Kurosawa, Hirofumi Ohashi, Seiji Mizuno, Tsutomu Ogata, Shigeo Kure, Tetsuya Niihori, Yoichi Matsubara

    American journal of medical genetics. Part A　158A　(5)　1083-94　2012/05

    DOI： 10.1002/ajmg.a.35292 　

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    Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, and intellectual disability. Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome. Since the discovery of the causative genes, approximately 150 new patients with each syndrome have been reported. However, the clinico-epidemiological features of these disorders remain to be identified. In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan. Based on the result of our survey, we estimated a total number of patients with either Costello syndrome or CFC syndrome in Japan of 99 (95% confidence interval, 77-120) and 157 (95% confidence interval, 86-229), respectively. The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively. An evaluation of 15 adult patients 18-32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. These results suggested that the number of adult patients is likely underestimated and our results represent a minimum prevalence. This is the first epidemiological study of Costello syndrome and CFC syndrome. Identifying patients older than 32 years of age and following up on the patients reported here is important to estimate the precise prevalence and the natural history of these disorders.

  136. Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. International-journal Peer-reviewed

    Ayumi Narisawa, Shoko Komatsuzaki, Atsuo Kikuchi, Tetsuya Niihori, Yoko Aoki, Kazuko Fujiwara, Mitsuyo Tanemura, Akira Hata, Yoichi Suzuki, Caroline L Relton, James Grinham, Kit-Yi Leung, Darren Partridge, Alexis Robinson, Victoria Stone, Peter Gustavsson, Philip Stanier, Andrew J Copp, Nicholas D E Greene, Teiji Tominaga, Yoichi Matsubara, Shigeo Kure

    Human molecular genetics　21　(7)　1496-503　2012/04/01

    DOI： 10.1093/hmg/ddr585 　

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    Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects of the central nervous system. The complex multigenic causation of human NTDs, together with the large number of possible candidate genes, has hampered efforts to delineate their molecular basis. Function of folate one-carbon metabolism (FOCM) has been implicated as a key determinant of susceptibility to NTDs. The glycine cleavage system (GCS) is a multi-enzyme component of mitochondrial folate metabolism, and GCS-encoding genes therefore represent candidates for involvement in NTDs. To investigate this possibility, we sequenced the coding regions of the GCS genes: AMT, GCSH and GLDC in NTD patients and controls. Two unique non-synonymous changes were identified in the AMT gene that were absent from controls. We also identified a splice acceptor site mutation and five different non-synonymous variants in GLDC, which were found to significantly impair enzymatic activity and represent putative causative mutations. In order to functionally test the requirement for GCS activity in neural tube closure, we generated mice that lack GCS activity, through mutation of AMT. Homozygous Amt(-/-) mice developed NTDs at high frequency. Although these NTDs were not preventable by supplemental folic acid, there was a partial rescue by methionine. Overall, our findings suggest that loss-of-function mutations in GCS genes predispose to NTDs in mice and humans. These data highlight the importance of adequate function of mitochondrial folate metabolism in neural tube closure.

  137. Epilepsy in RAS/MAPK syndrome: Two cases of cardio-facio-cutaneous syndrome with epileptic encephalopathy and a literature review Peer-reviewed

    Masao Adachi, Yu Abe, Yoko Aoki, Yoichi Matsubara

    SEIZURE-EUROPEAN JOURNAL OF EPILEPSY　21　(1)　55-60　2012/01

    DOI： 10.1016/j.seizure.2011.07.013 　

    ISSN： 1059-1311

  138. Non-hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome. International-journal Peer-reviewed

    Akira Ohtake, Yoko Aoki, Yuka Saito, Tetsuya Niihori, Atsushi Shibuya, Shigeo Kure, Yoichi Matsubara

    Journal of pediatric hematology/oncology　33　(8)　e342-6-6　2011/12

    DOI： 10.1097/MPH.0b013e3181df5e5b 　

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    Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. BRAF mutations are involved in more than 80% of CFC syndrome patients, and we have reported earlier that 2 CFC patients with BRAF mutations developed acute lymphoblastic leukemia. Here we report a boy with CFC syndrome who developed non-Hodgkin lymphoma. At 2 months of age, he developed pneumonia with pleurisy and was diagnosed as having non-Hodgkin lymphoma (precursor T-cell lymphoblastic lymphoma) by cytopathologic examination of the pleural fluid. He was suspected of having Noonan syndrome because of his facial appearance, webbed neck, and cubitus valgus. Precursor T-cell lymphoblastic lymphoma was treated by the TCCSG NHL 94-04 protocol. At 9 years of age, he was clinically reevaluated and diagnosed as having CFC syndrome because of his distinctive facial appearance, multiple nevi, and moderate mental retardation. Sequencing analysis showed a germline p.A246P (c.736G>C) mutation in BRAF reported earlier in CFC syndrome. Molecular diagnosis and careful observation should be considered in children with CFC syndrome.

  139. Implantable Cardioverter Defibrillator for Progressive Hypertrophic Cardiomyopathy in a Patient With LEOPARD Syndrome and a Novel PTPN11 Mutation Gln510His Peer-reviewed

    Yasushi Wakabayashi, Kyohei Yamazaki, Yoko Narumi, Satoshi Fuseya, Miki Horigome, Keiko Wakui, Yoshimitsu Fukushima, Yoichi Matsubara, Yoko Aoki, Tomoki Kosho

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　155A　(10)　2529-2533　2011/10

    DOI： 10.1002/ajmg.a.34194 　

    ISSN： 1552-4825

  140. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. International-journal Peer-reviewed

    Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto, Kenji Kurosawa, Hirofumi Ohashi, Seiji Mizuno, Hiroshi Kawame, Johji Inazawa, Toshihiro Ohura, Hiroshi Arai, Shin Nabatame, Kiyoshi Kikuchi, Yoshikazu Kuroki, Masaru Miura, Toju Tanaka, Akira Ohtake, Isaku Omori, Kenji Ihara, Hiroyo Mabe, Kyoko Watanabe, Shinichi Niijima, Erika Okano, Hironao Numabe, Yoichi Matsubara

    Journal of human genetics　56　(10)　707-15　2011/10

    DOI： 10.1038/jhg.2011.85 　

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    Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

  141. A familial case of LEOPARD syndrome associated with a high-functioning autism spectrum disorder. International-journal Peer-reviewed

    Yoriko Watanabe, Shoji Yano, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Makoto Yoshino, Toyojiro Matsuishi

    Brain & development　33　(7)　576-9　2011/08

    DOI： 10.1016/j.braindev.2010.10.006 　

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    A connection between LEOPARD syndrome (a rare autosomal dominant disorder) and autism spectrum disorders (ASDs) may exist. Of four related individuals (father and three sons) with LEOPARD syndrome, all patients exhibited clinical symptoms consistent with ASDs. Findings included aggressive behavior and impairment of social interaction, communication, and range of interests. The coexistence of LEOPARD syndrome and ASDs in the related individuals may be an incidental familial event or indicative that ASDs is associated with LEOPARD syndrome. There have been no other independent reports of the association of LEOPARD syndrome and ASDs. Molecular and biochemical mechanisms that may suggest a connection between LEOPARD syndrome and ASDs are discussed.

  142. 5番染色体短腕部分欠失にマーカー染色体を伴う染色体異常が検出された一例

    小林 朋子, 青木 洋子, 松田 直, 新堀 哲也, 土屋 滋, 松原 洋一

    日本小児科学会雑誌　115　(2)　384-384　2011/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  143. Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination Peer-reviewed

    Koichi Aizaki, Kenji Sugai, Yoshiaki Saito, Eiji Nakagawa, Masayuki Sasaki, Yoko Aoki, Yoichi Matsubara

    BRAIN & DEVELOPMENT　33　(2)　166-169　2011/02

    DOI： 10.1016/j.braindev.2010.03.008 　

    ISSN： 0387-7604

  144. Implications of Prenatal Diagnosis of the Fetus With Both Interstitial Deletion and a Small Marker Ring Originating From Chromosome 5 Peer-reviewed

    Hiroyasu Ohashi, Kaoru Suzumori, Yasushi Chisaka, Shinichi Sonta, Tomoko Kobayashi, Yoko Aoki, Yoichi Matsubara, Michiko Sone, Lisa G. Shaffer

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　155A　(1)　192-196　2011/01

    DOI： 10.1002/ajmg.a.33764 　

    ISSN： 1552-4825

  145. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. International-journal Peer-reviewed

    Shoko Komatsuzaki, Yoko Aoki, Tetsuya Niihori, Nobuhiko Okamoto, Raoul C M Hennekam, Saskia Hopman, Hirofumi Ohashi, Seiji Mizuno, Yoriko Watanabe, Hotaka Kamasaki, Ikuko Kondo, Nobuko Moriyama, Kenji Kurosawa, Hiroshi Kawame, Ryuhei Okuyama, Masue Imaizumi, Takeshi Rikiishi, Shigeru Tsuchiya, Shigeo Kure, Yoichi Matsubara

    Journal of human genetics　55　(12)　801-9　2010/12

    DOI： 10.1038/jhg.2010.116 　

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    Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative for a type of Noonan-like syndrome characterized by the presence of loose anagen hair. In order to understand the contribution of SHOC2 mutations to the clinical manifestations of Noonan syndrome and related disorders, we analyzed SHOC2 in 92 patients with Noonan syndrome and related disorders who did not exhibit PTPN11, KRAS, HRAS, BRAF, MAP2K1/2, SOS1 or RAF1 mutations. We found the previously identified p.S2G mutation in eight of our patients. We developed a rapid detection system to identify the p.S2G mutation using melting curve analysis, which will be a useful tool to screen for the apparently common mutation. All the patients with the p.S2G mutation showed short stature, sparse hair and atopic skin. Six of the mutation-positive patients showed severe mental retardation and easily pluckable hair, and one showed leukocytosis. No SHOC2 mutations were identified in leukemia cells from 82 leukemia patients. These results suggest that clinical manifestations in SHOC2 mutation-positive patients partially overlap with those in patients with typical Noonan or CFC syndrome and show that easily pluckable/loose anagen hair is distinctive in SHOC2 mutation-positive patients.

  146. Clinical and genetic features of 20 Japanese patients with vascular-type Ehlers-Danlos syndrome Peer-reviewed

    Y. Shimaoka, T. Kosho, M. Wataya-Kaneda, M. Funakoshi, T. Suzuki, S. Hayashi, Y. Mitsuhashi, T. Isei, Y. Aoki, K. Yamazaki, M. Ono, K. Makino, T. Tanaka, E. Kunii, A. Hatamochi

    BRITISH JOURNAL OF DERMATOLOGY　163　(4)　704-710　2010/10

    DOI： 10.1111/j.1365-2133.2010.09874.x 　

    ISSN： 0007-0963

  147. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. International-journal Peer-reviewed

    Tomoko Kobayashi, Yoko Aoki, Tetsuya Niihori, Hélène Cavé, Alain Verloes, Nobuhiko Okamoto, Hiroshi Kawame, Ikuma Fujiwara, Fumio Takada, Takako Ohata, Satoru Sakazume, Tatsuya Ando, Noriko Nakagawa, Pablo Lapunzina, Antonio G Meneses, Gabriele Gillessen-Kaesbach, Dagmar Wieczorek, Kenji Kurosawa, Seiji Mizuno, Hirofumi Ohashi, Albert David, Nicole Philip, Afag Guliyeva, Yoko Narumi, Shigeo Kure, Shigeru Tsuchiya, Yoichi Matsubara

    Human mutation　31　(3)　284-94　2010/03

    DOI： 10.1002/humu.21187 　

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    Noonan syndrome (NS) and related disorders are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. The dysregulation of the RAS/MAPK pathway appears to be a common molecular pathogenesis of these disorders: mutations in PTPN11, KRAS, and SOS1 have been identified in patients with NS, those in KRAS, BRAF, MAP2K1, and MAP2K2 in patients with CFC syndrome, and those in HRAS mutations in Costello syndrome patients. Recently, mutations in RAF1 have been also identified in patients with NS and two patients with LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In the current study, we identified eight RAF1 mutations in 18 of 119 patients with NS and related conditions without mutations in known genes. We summarized clinical manifestations in patients with RAF1 mutations as well as those in NS patients withPTPN11, SOS1, or KRAS mutations previously reported. Hypertrophic cardiomyopathy and short stature were found to be more frequently observed in patients with RAF1 mutations. Mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (serine at position 259; S259). Functional studies revealed that the RAF1 mutants located in the CR2 domain resulted in the decreased phosphorylation of S259, and that mutant RAF1 then dissociated from 14-3-3, leading to a partial ERK activation. Our results suggest that the dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well as of downstream ERK.

  148. Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: From bedside to bench and back Peer-reviewed

    Katherine A. Rauen, Lisa Schoyer, Frank McCormick, Angela E. Lin, Judith E. Allanson, David A. Stevenson, Karen W. Gripp, Giovanni Neri, John C. Carey, Eric Legius, Marco Tartaglia, Suzanne Schubbert, Amy E. Roberts, Bruce D. Gelb, Kevin Shannon, David H. Gutmann, Martin McMahon, Carmen Guerra, James A. Fagin, Benjamin Yu, Yoko Aoki, Benjamin G. Neel, Allan Balmain, Richard R. Drake, Garry P. Nolan, Martin Zenker, Gideon Bollag, Judith Sebolt-Leopold, Jackson B. Gibbs, Alcino J. Silva, E. Elizabeth Patton, David H. Viskochil, Mark W. Kieran, Bruce R. Korf, Randi J. Hagerman, Roger J. Packer, Teri Melese

    American Journal of Medical Genetics, Part A　152　(1)　4-24　2010/01

    DOI： 10.1002/ajmg.a.33183 　

    ISSN： 1552-4825 1552-4833

  149. 23歳時の貧血精査で診断された、骨髄染色体45、X、末梢血染色体45、X/47、XXXを呈したTurner症候群の1例

    菅野 潤子, 水城 弓絵, 斉藤 明子, 大野 忠行, 森本 哲司, 藤原 幾磨, 土屋 滋, 小松崎 匠子, 新堀 哲也, 青木 洋子, 松原 洋一

    日本小児科学会雑誌　113　(9)　1445-1445　2009/09

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  150. Model mice for mild-form glycine encephalopathy: Behavioral and biochemical characterizations and efficacy of antagonists for the glycine binding site of N-methyl D-aspartate receptor Peer-reviewed

    Kanako Kojima-Ishii, Shigeo Kure, Aktko Ichinohe, Toshikatsu Shinka, Ayumi Narisawa, Show Komatsuzaki, Junnko Kanno, Fumiaki Kamada, Yoko Aoki, Hiroyuki Yokoyama, Masaya Oda, Taku Sugawara, Kazuo Mizoi, Daiichiro Nakahara, Yoichi Matsubara

    PEDIATRIC RESEARCH　64　(3)　228-233　2008/09

    DOI： 10.1203/PDR.0b013e3181799562 　

    ISSN： 0031-3998

  151. Association of the GABRB3 gene with nonsyndromic oral clefts Peer-reviewed

    Hiroki Inoue, Shuji Kayano, Yoko Aoki, Shigeo Kure, Atsushi Yamada, Akira Hata, Yoichi Matsubara, Yoichi Suzuki

    CLEFT PALATE-CRANIOFACIAL JOURNAL　45　(3)　261-266　2008/05

    DOI： 10.1597/06-142R1.1 　

    ISSN： 1055-6656

  152. Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. International-journal Peer-reviewed

    Yoko Narumi, Yoko Aoki, Tetsuya Niihori, Masahiro Sakurai, Hélène Cavé, Alain Verloes, Kimio Nishio, Hirofumi Ohashi, Kenji Kurosawa, Nobuhiko Okamoto, Hiroshi Kawame, Seiji Mizuno, Tatsuro Kondoh, Marie-Claude Addor, Anne Coeslier-Dieux, Catherine Vincent-Delorme, Koichi Tabayashi, Masashi Aoki, Tomoko Kobayashi, Afag Guliyeva, Shigeo Kure, Yoichi Matsubara

    Journal of human genetics　53　(9)　834-41　2008

    DOI： 10.1007/s10038-008-0320-0 　

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    Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.

  153. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. International-journal Peer-reviewed

    Caroline Nava, Nadine Hanna, Caroline Michot, Sabrina Pereira, Nathalie Pouvreau, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Benoit Arveiler, Didier Lacombe, Eric Pasmant, Béatrice Parfait, Clarisse Baumann, Delphine Héron, Sabine Sigaudy, Annick Toutain, Marlène Rio, Alice Goldenberg, Bruno Leheup, Alain Verloes, Hélène Cavé

    Journal of medical genetics　44　(12)　763-71　2007/12

    DOI： 10.1136/jmg.2007.050450 　

    eISSN： 1468-6244

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    Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.

  154. Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis. International-journal Peer-reviewed

    Kanno Junko, Kure Shigeo, Narisawa Ayumi, Kamada Fumiaki, Takayanagi Masaru, Yamamoto Katsuya, Hoshino Hisao, Goto Tomohide, Takahashi Takao, Haginoya Kazuhiro, Tsuchiya Shigeru, Baumeister Fritz A M, Hasegawa Yuki, Aoki Yoko, Yamaguchi Seiji, Matsubara Yoichi

    Mol Genet Metab　91　(4)　384-389　2007/08

    DOI： 10.1016/j.ymgme.2007.02.010 　

    ISSN： 1096-7192

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    Pyridoxine dependent seizure (PDS) is a disorder of neonates or infants with autosomal recessive inheritance characterized by seizures, which responds to pharmacological dose of pyridoxine. Recently, mutations have been identified in the ALDH7A1 gene in Caucasian families with PDS. To elucidate further the genetic background of PDS, we screened for ALDH7A1 mutations in five PDS families (patients 1-5) that included four Orientals. Diagnosis as having PDS was confirmed by pyridoxine-withdrawal test. Exon sequencing analysis of patients 1-4 revealed eight ALDH7A1 mutations in compound heterozygous forms: five missense mutations, one nonsense mutation, one point mutation at the splicing donor site in intron 1, and a 1937-bp genomic deletion. The deletion included the entire exon 17, which was flanked by two Alu elements in introns 16 and 17. None of the mutations was found in 100 control chromosomes. In patient 5, no mutation was found by the exon sequencing analysis. Furthermore, expression level or nucleotide sequences of ALDH7A1 mRNA in lymphoblasts were normal. Plasma pipecolic acid concentration was not elevated in patient 5. These observations suggest that ALDH7A1 mutation is unlikely to be responsible for patient 5. Abnormal metabolism of GABA/glutamate in brain has long been suggested as the underlying pathophysiology of PDS. CSF glutamate concentration was elevated during the off-pyridoxine period in patient 3, but not in patient 2 or 5. These results suggest allelic and non-allelic heterogeneities of PDS, and that the CSF glutamate elevation does not directly correlate with the presence of ALDH7A1 mutations.

  155. Direct correlation between ischemic injury and extracellular glycine concentration in mice with genetically altered activities of the glycine cleavage multienzyme system Peer-reviewed

    Masaya Oda, Shigeo Kure, Taku Sugawara, Suguru Yamaguchi, Kanako Kojima, Toshikatsu Shinka, Kenichi Sato, Ayumi Narisawa, Yoko Aoki, Yoichi Matsubara, Tomoya Omae, Kazuo Mizoi, Hiroyuki Kinouchi

    STROKE　38　(7)　2157-2164　2007/07

    DOI： 10.1161/STROKEAHA.106.477026 　

    ISSN： 0039-2499

  156. Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. International-journal Peer-reviewed

    Yoshio Makita, Yoko Narumi, Makoto Yoshida, Tetsuya Niihori, Shigeo Kure, Kenji Fujieda, Yoichi Matsubara, Yoko Aoki

    Journal of pediatric hematology/oncology　29　(5)　287-90　2007/05

    DOI： 10.1097/MPH.0b013e3180547136 　

    ISSN： 1077-4114

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    Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in 2 genes that encode molecules of the RAS/MAPK (mitogen activated protein kinase) pathway (PTPN11 and HRAS, respectively). Recently, mutations in KRAS, BRAF, and MEK1/2 have been identified in patients with CFC syndrome. Somatic mutations in KRAS and BRAF have been identified in various tumors. In contrast, the association with malignancy has not been noticed in CFC syndrome. Here we report a 9-year-old boy diagnosed with CFC syndrome and acute lymphoblastic leukemia. Sequencing analysis of the entire coding region of KRAS and BRAF showed a de novo germline BRAF E501G (1502A-->G) mutation. Molecular diagnosis and careful observations should be considered in children with CFC syndrome because they have germline mutations in proto-oncogenes and might develop malignancy.

  157. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. International-journal Peer-reviewed

    Yoko Narumi, Yoko Aoki, Tetsuya Niihori, Giovanni Neri, Hélène Cavé, Alain Verloes, Caroline Nava, Maria Ines Kavamura, Nobuhiko Okamoto, Kenji Kurosawa, Raoul C M Hennekam, Louise C Wilson, Gabriele Gillessen-Kaesbach, Dagmar Wieczorek, Pablo Lapunzina, Hirofumi Ohashi, Yoshio Makita, Ikuko Kondo, Shigeru Tsuchiya, Etsuro Ito, Kiyoko Sameshima, Kumi Kato, Shigeo Kure, Yoichi Matsubara

    American journal of medical genetics. Part A　143A　(8)　799-807　2007/04/15

    DOI： 10.1002/ajmg.a.31658 　

    ISSN： 1552-4825

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    Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.

  158. Genomic deletion within GLDC is a major cause of non-ketotic hyperglycinaemia Peer-reviewed

    Junko Kanno, Tim Hutchin, Fumiaki Kamada, Ayumi Narisawa, Yoko Aoki, Yoichi Matsubara, Shigeo Kure

    JOURNAL OF MEDICAL GENETICS　44　(3)　e69-e69　2007/03

    DOI： 10.1136/jmg.2006.043448 　

    ISSN： 0022-2593

  159. Rapid diagnosis of glycine encephalopathy by C-13-glycine breath test Peer-reviewed

    S Kure, SH Korman, J Kanno, A Narisawa, M Kubota, T Takayanagi, M Takayanagi, T Saito, A Matsui, F Kamada, Y Aoki, T Ohura, Y Matsubara

    ANNALS OF NEUROLOGY　59　(5)　862-867　2006/05

    DOI： 10.1002/ana.20853 　

    ISSN： 0364-5134

  160. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia Peer-reviewed

    S Kure, K Kato, A Dinopoulos, C Gail, TJ deGrauw, J Christodoulou, Bzduch, V, R Kalmanchey, G Fekete, A Trojovsky, B Plecko, G Breningstall, J Tohyama, Y Aoki, Y Matsubara

    HUMAN MUTATION　27　(4)　343-352　2006/04

    DOI： 10.1002/humu.20293 　

    ISSN： 1059-7794

  161. HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation Peer-reviewed

    KW Gripp, AE Lin, DL Stabley, L Nicholson, CI Scott, D Doyle, Y Aoki, Y Matsubara, EH Zackai, P Lapunzina, A Gonzalez-Meneses, J Holbrook, CA Agresta, IL Gonzalez, K Sol-Church

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　140A　(1)　1-7　2006/01

    DOI： 10.1002/ajmg.a.31047 　

    ISSN： 1552-4825

  162. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation. International-journal Peer-reviewed

    Fumiaki Kamada, Shigeo Kure, Takayuki Kudo, Yoichi Suzuki, Takeshi Oshima, Akiko Ichinohe, Kanako Kojima, Tetsuya Niihori, Junko Kanno, Yoko Narumi, Ayumi Narisawa, Kumi Kato, Yoko Aoki, Katsuhisa Ikeda, Toshimitsu Kobayashi, Yoichi Matsubara

    Journal of human genetics　51　(5)　455-60　2006

    DOI： 10.1007/s10038-006-0384-7 　

    ISSN： 1434-5161

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    Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.

  163. Adult Alexander's disease without leukoencephalopathy Peer-reviewed

    F Salvi, Y Aoki, R Della Nave, A Vella, F Pastorelli, C Scaglione, Y Matsubara, M Mascalchi

    ANNALS OF NEUROLOGY　58　(5)　813-814　2005/11

    DOI： 10.1002/ana.20634 　

    ISSN： 0364-5134

  164. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia Peer-reviewed

    T Niihori, Y Aoki, H Ohashi, K Kurosawa, T Kondoh, S Ishikiriyama, H Kawame, H Kamasaki, T Yamanaka, F Takada, K Nishio, M Sakurai, H Tamai, T Nagashima, Y Suzuki, S Kure, K Fujii, M Imaizumi, Y Matsubara

    JOURNAL OF HUMAN GENETICS　50　(4)　192-202　2005/04

    DOI： 10.1007/s10038-005-0239-7 　

    ISSN： 1435-232X

  165. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. International-journal Peer-reviewed

    Tetsuya Niihori, Yoko Aoki, Hirofumi Ohashi, Kenji Kurosawa, Tatsuro Kondoh, Satoshi Ishikiriyama, Hiroshi Kawame, Hotaka Kamasaki, Tsutomu Yamanaka, Fumio Takada, Kimio Nishio, Masahiro Sakurai, Hiroshi Tamai, Tatsuro Nagashima, Yoichi Suzuki, Shigeo Kure, Kunihiro Fujii, Masue Imaizumi, Yoichi Matsubara

    Journal of human genetics　50　(4)　192-202　2005

    DOI： 10.1007/s10038-005-0239-7 　

    ISSN： 1434-5161

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    Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis.

  166. Association of the hCLCA1 gene with childhood and adult asthma Peer-reviewed

    F Kamada, Y Suzuki, C Shao, M Tamari, K Hasegawa, T Hirota, M Shimizu, N Takahashi, XQ Mao, S Doi, H Fujiwara, A Miyatake, K Fujita, Y Chiba, Y Aoki, S Kure, G Tamura, T Shirakawa, Y Matsubara

    GENES AND IMMUNITY　5　(7)　540-547　2004/11

    DOI： 10.1038/sj.gene.6364124 　

    ISSN： 1466-4879

  167. Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT). Peer-reviewed

    Kayano S, Suzuki Y, Kanno K, Aoki Y, Kure S, Yamada A, Matsubara Y

    American journal of medical genetics. Part A　130A　(1)　40-44　2004/09

    DOI： 10.1002/ajmg.a.30023 　

    ISSN： 1552-4825

  168. Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency Peer-reviewed

    S Kure, K Sato, K Fujii, Y Aoki, Y Suzuki, S Kato, Y Matsubara

    MOLECULAR GENETICS AND METABOLISM　83　(1-2)　150-156　2004/09

    DOI： 10.1016/j.ymgme.2004.06.016 　

    ISSN： 1096-7192

  169. Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT) Peer-reviewed

    S Kayano, Y Suzuki, K Kanno, Y Aoki, S Kure, A Yamada, Y Matsubara

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　130A　(1)　40-44　2004/09

    DOI： 10.1002/ajmg.a.30023 　

    ISSN： 0148-7299

  170. Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B-12-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation Peer-reviewed

    Yang, X, O Sakamoto, Y Matsubara, S Kure, Y Suzuki, Y Aoki, Y Suzuki, N Sakura, M Takayanagi, K Iinuma, T Ohura

    MOLECULAR GENETICS AND METABOLISM　82　(4)　329-333　2004/08

    DOI： 10.1016/j.ymgme.2004.05.002 　

    ISSN： 1096-7192

  171. Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population Peer-reviewed

    Kiyoshi Kanno, Yoichi Suzuki, Atsushi Yamada, Yoko Aoki, Shigeo Kure, Yoichi Matsubara

    American Journal of Medical Genetics　127　(1)　11-16　2004/05/15

    DOI： 10.1002/ajmg.a.20649 　

    ISSN： 1552-4825

  172. Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population Peer-reviewed

    K Kanno, Y Suzuki, A Yamada, Y Aoki, S Kure, Y Matsubara

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　127A　(1)　11-16　2004/05

    DOI： 10.1002/ajmg.a.20649 　

    ISSN： 0148-7299

  173. Genetic testing of glycogen storage disease type Ib in Japan: five novel G6PT1 mutations and a rapid detection method for a prevalent mutation W118R Peer-reviewed

    K Kojima, S Kure, F Kamada, K Hao, A Ichinohe, K Sato, Y Aoki, S Yoichi, M Kubota, R Horikawa, A Utsumi, M Miura, S Ogawa, M Kanazawa, Y Kohno, M Inokuchi, T Hasegawa, K Narisawa, Y Matsubara

    MOLECULAR GENETICS AND METABOLISM　81　(4)　343-346　2004/04

    DOI： 10.1016/j.ymgme.2003.12.004 　

    ISSN： 1096-7192

  174. Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia Peer-reviewed

    Yang, X, O Sakamoto, Y Matsubara, S Kure, Y Suzuki, Y Aoki, S Yamaguchi, Y Takahashi, T Nishikubo, C Kawaguchi, A Yoshioka, T Kimura, K Hayasaka, Y Kohno, K Iinuma, T Ohura

    MOLECULAR GENETICS AND METABOLISM　81　(4)　335-342　2004/04

    DOI： 10.1016/j.ymgme.2004.01.003 　

    ISSN： 1096-7192

  175. Linkage and association of childhood asthma with the chromosome 12 genes Peer-reviewed

    CC Shao, Y Suzuki, F Kamada, K Kanno, M Tamari, K Hasegawa, Y Aoki, S Kure, Yang, X, H Endo, R Takayanagi, C Nakazawa, T Morikawa, M Morikawa, S Miyabayashi, Y Chiba, M Karahashi, S Saito, G Tamura, T Shirakawa, Y Matsubara

    JOURNAL OF HUMAN GENETICS　49　(3)　115-122　2004/03

    DOI： 10.1007/s10038-003-0118-z 　

    ISSN： 1435-232X

  176. Novel IRF6 mutations in Japanese patients with Van der Woude Syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion Peer-reviewed

    S Kayano, S Kure, Y Suzuki, K Kanno, Y Aoki, S Kondo, BC Schutte, JC Murray, A Yamada, Y Matsubara

    JOURNAL OF HUMAN GENETICS　48　(12)　622-628　2003/12

    DOI： 10.1007/s10038-003-0089-0 　

    ISSN： 1435-232X

  177. Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report Peer-reviewed

    T Kondoh, E Ishii, Y Aoki, T Shimizu, M Zaitsu, Y Matsubara, H Moriuchi

    EUROPEAN JOURNAL OF PEDIATRICS　162　(7-8)　548-549　2003/07

    DOI： 10.1007/s00431-003-1227-6 　

    ISSN： 0340-6199

  178. Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects Peer-reviewed

    R Santer, H Muhle, T Suormala, ER Baumgartner, M Duran, Yang, X, Y Aoki, Y Suzuki, U Stephani

    MOLECULAR GENETICS AND METABOLISM　79　(3)　160-166　2003/07

    DOI： 10.1016/S1096-7192(03)00091-X 　

    ISSN： 1096-7192

  179. Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness Peer-reviewed

    T Kudo, S Kure, K Ikeda, AP Xia, Y Katori, M Suzuki, K Kojima, A Ichinohe, Y Suzuki, Y Aoki, T Kobayashi, Y Matsubara

    HUMAN MOLECULAR GENETICS　12　(9)　995-1004　2003/05

    DOI： 10.1093/hmg/ddg116 　

    ISSN： 0964-6906

  180. Identification of GFAP gene mutation in hereditary adult-onset Alexander's disease Peer-reviewed

    M Namekawa, Y Takiyama, Y Aoki, N Takayashiki, K Sakoe, H Shimazaki, T Taguchi, Y Tanaka, M Nishizawa, K Saito, Y Matsubara, Nakano, I

    ANNALS OF NEUROLOGY　52　(6)　779-785　2002/12

    DOI： 10.1002/ana.10375 　

    ISSN： 0364-5134

  181. Heterozygous GLDC and GCSH gene mutations in transient neonatal hyperglycinemia Peer-reviewed

    S Kure, K Kojima, A Ichinohe, T Maeda, R Kalmanchey, G Fekete, SZ Berg, J Filiano, Y Aoki, Y Suzuki, T Izumi, Y Matsubara

    ANNALS OF NEUROLOGY　52　(5)　643-646　2002/11

    DOI： 10.1002/ana.10367 　

    ISSN： 0364-5134

  182. Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor alpha gene in the Japanese population Peer-reviewed

    K Kanno, Y Suzuki, XM Yang, A Yamada, Y Aoki, S Kure, Y Matsubara

    JOURNAL OF HUMAN GENETICS　47　(6)　269-274　2002

    DOI： 10.1007/s100380200038 　

    ISSN： 1434-5161

  183. Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency Peer-reviewed

    Yang, X, Y Aoki, Li, X, O Sakamoto, M Hiratsuka, S Kure, S Taheri, E Christensen, K Inui, M Kubota, M Ohira, M Ohki, J Kudoh, K Kawasaki, K Shibuya, A Shintani, S Asakawa, S Minoshima, N Shimizu, K Narisawa, Y Matsubara, Y Suzuki

    HUMAN GENETICS　109　(5)　526-534　2001/11

    DOI： 10.1007/s004390100603 　

    ISSN： 0340-6717

  184. Structure and expression of the glycine cleavage system in rat central nervous system Peer-reviewed

    Y Sakata, Y Owada, K Sato, K Kojima, K Hisanaga, T Shinka, Y Suzuki, Y Aoki, J Satoh, H Kondo, Y Matsubara, S Kure

    MOLECULAR BRAIN RESEARCH　94　(1-2)　119-130　2001/10

    DOI： 10.1016/S0169-328X(01)00225-X 　

    ISSN： 0169-328X

  185. A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease Peer-reviewed

    Y Aoki, K Haginoya, M Munakata, H Yokoyama, T Nishio, N Togashi, T Ito, Y Suzuki, S Kure, K Iinuma, M Brenner, Y Matsubara

    NEUROSCIENCE LETTERS　312　(2)　71-74　2001/10

    DOI： 10.1016/S0304-3940(01)02139-5 　

    ISSN： 0304-3940

  186. Fatal Propionic Acidemia in Mice Lacking Propionyl-CoA Carboxylase and Its Rescue by Postnatal, Liver-specific Supplementation via a Transgene Peer-reviewed

    Toru Miyazaki, Toshihiro Ohura, Makio Kobayashi, Yosuke Shigematsu, Seiji Yamaguchi, Yoichi Suzuki, Ikue Hata, Yoko Aoki, Xue Yang, Christina Minjares, Ikuko Haruta, Hirofumi Uto, Yuriko Ito, Urs Müller

    Journal of Biological Chemistry　276　(38)　35995-35999　2001/09/21

    DOI： 10.1074/jbc.M105467200 　

    ISSN： 0021-9258

  187. Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia Peer-reviewed

    S Kure, K Kojima, T Kudo, K Kanno, Y Aoki, Y Suzuki, T Shinka, Y Sakata, K Narisawa, Y Matsubara

    JOURNAL OF HUMAN GENETICS　46　(7)　378-384　2001

    DOI： 10.1007/s100380170057 　

    ISSN： 1434-5161

  188. Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2 Peer-reviewed

    Y Aoki, ZH Huang, SS Thomas, PG Bhide, Huang, I, MA Moskowitz, SA Reeves

    FASEB JOURNAL　14　(13)　1965-1973　2000/10

    DOI： 10.1096/fj.00-0105com 　

    ISSN： 0892-6638

  189. Heterogeneous mutations in the glucose-6-phosphatase gene in Japanese patients with glycogen storage disease type Ia Peer-reviewed

    K Takahashi, J Akanuma, Y Matsubara, K Fujii, S Kure, Y Suzuki, K Wataya, O Sakamoto, Y Aoki, M Ogasawara, T Ohura, S Miyabayashi, K Narisawa

    AMERICAN JOURNAL OF MEDICAL GENETICS　92　(2)　90-94　2000/05

    DOI： 10.1002/(SICI)1096-8628(20000515)92:2<90::AID-AJMG2>3.0.CO;2-H 　

    ISSN： 0148-7299

  190. Diagnosis and molecular analysis of an atypical case of holocarboxylase synthetase deficiency Peer-reviewed

    O Sakamoto, Y Suzuki, Li, X, Y Aoki, M Hiratsuka, E Holme, J Kudoh, N Shimizu, K Narisawa

    EUROPEAN JOURNAL OF PEDIATRICS　159　(1-2)　18-22　2000/01

    ISSN： 0340-6199

  191. Haplotype analysis suggests that the two predominant mutations in Japanese patients with holocarboxylase synthetase deficiency are founder mutations Peer-reviewed

    Yang, X, Y Aoki, Li, X, O Sakamoto, M Hiratsuka, KM Gibson, S Kure, K Narisawa, Y Matsubara, Y Suzuki

    JOURNAL OF HUMAN GENETICS　45　(6)　358-362　2000

    DOI： 10.1007/s100380070008 　

    ISSN： 1434-5161

  192. Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in holocarboxylase synthetase deficiency Peer-reviewed

    O Sakamoto, Y Suzuki, Li, X, Y Aoki, M Hiratsuka, T Suormala, ER Baumgartner, KM Gibson, K Narisawa

    PEDIATRIC RESEARCH　46　(6)　671-676　1999/12

    ISSN： 0031-3998

  193. Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency Peer-reviewed

    Y Aoki, Li, X, O Sakamoto, M Hiratsuka, H Akaishi, LQ Xu, P Briones, T Suormala, ER Baumgartner, Y Suzuki, K Narisawa

    HUMAN GENETICS　104　(2)　143-148　1999/02

    DOI： 10.1007/s004390050927 　

    ISSN： 0340-6717

  194. Molecular analysis of new Japanese patients with holocarboxylase synthetase deficiency Peer-reviewed

    O Sakamoto, Y Suzuki, Y Aoki, Li, X, M Hiratsuka, K Yanagihara, K Inui, T Okabe, S Yamaguchi, J Kudoh, N Shimizu, K Narisawa

    JOURNAL OF INHERITED METABOLIC DISEASE　21　(8)　873-874　1998/12

    DOI： 10.1023/A:1005435121933 　

    ISSN： 0141-8955

  195. Identification of holocarboxylase synthetase (HCS) proteins in human placenta Peer-reviewed

    M Hiratsuka, O Sakamoto, Li, X, Y Suzuki, Y Aoki, K Narisawa

    BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY　1385　(1)　165-171　1998/06

    DOI： 10.1016/S0167-4838(98)00032-6 　

    ISSN： 0167-4838

  196. Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2 Peer-reviewed

    T Servidei, Y Aoki, SE Lewis, A Symes, JS Fink, SA Reeves

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(11)　6233-6241　1998/03

    DOI： 10.1074/jbc.273.11.6233 　

    ISSN： 0021-9258

  197. Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: Functional analysis and association with polymorphic haplotypes and two clinical phenotypes Peer-reviewed

    K Wataya, J Akanuma, P Cavadini, Y Aoki, S Kure, F Invernizzi, Yoshida, I, J Kira, F Taroni, Y Matsubara, K Narisawa

    HUMAN MUTATION　11　(5)　377-386　1998

    DOI： 10.1002/(SICI)1098-1004(1998)11:5<377::AID-HUMU5>3.0.CO;2-E 　

    ISSN： 1059-7794

  198. Characterization of mutant holocarboxylase synthetase (HCS): A K-m for biotin was not elevated in a patient with HCS deficiency Peer-reviewed

    Y Aoki, Y Suzuki, Li, X, O Sakamoto, H Chikaoka, S Takita, K Narisawa

    PEDIATRIC RESEARCH　42　(6)　849-854　1997/12

    ISSN： 0031-3998

  199. Dinucleotide repeat polymorphism in 65k-Glutamate decarboxylase gene Peer-reviewed

    S Kure, Y Aoki, T Shinka, Y Sakata, Y Matsubara, K Narisawa

    JAPANESE JOURNAL OF HUMAN GENETICS　42　(3)　429-431　1997/09

    ISSN： 0916-8478

  200. Molecular analyses of Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS)

    Masashi Aoki, Koji Abe, Masahito Ogasawara, Yoko Aoki, Yoichi Matsubara, Kuniaki Narisawa, Mitsunori Watanabe, Masaki Ikeda, Kouji Houi, Soichiro Mocfflo, Katsuro Kurokawa, Takeo Kato, Hideo Sasaki, Ryo Sakuma, Takeshi Kameya, Shyozo Nakamura, Yasuto Itoyama

    Japanese Journal of Human Genetics　41　28　1996/12/01

    ISSN： 0916-8478

  201. Enzymatic diagnosis of holocarboxylase synthetase deficiency using apo-carboxyl carrier protein as a substrate Peer-reviewed

    Y Suzuki, Y Aoki, O Sakamoto, Li, X, S Miyabayashi, Y Kazuta, H Kondo, K Narisawa

    CLINICA CHIMICA ACTA　251　(1)　41-52　1996/07

    DOI： 10.1016/0009-8981(96)06291-2 　

    ISSN： 0009-8981

  202. Molecular analysis of holocarboxylase synthetase deficiency: A missense mutation and a single base deletion are predominant in Japanese patients Peer-reviewed

    Y Aoki, Y Suzuki, O Sakamoto, Li, X, K Takahashi, A Ohtake, R Sakuta, T Ohura, S Miyabayashi, K Narisawa

    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE　1272　(3)　168-174　1995/12

    ISSN： 0925-4439

  203. PURIFICATION AND PROPERTIES OF BOVINE LIVER HOLOCARBOXYLASE SYNTHETASE Peer-reviewed

    Y CHIBA, Y SUZUKI, Y AOKI, Y ISHIDA, K NARISAWA

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　313　(1)　8-14　1994/08

    DOI： 10.1006/abbi.1994.1351 　

    ISSN： 0003-9861

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  4. Dysregulation of RAS proteostasis induces tumor growth and metastasis

    阿部太紀, 菅野新一郎, 新堀哲也, 寺尾美穂, 高田修治, 青木洋子

    日本薬学会年会要旨集(Web)　144th　2024

    ISSN： 0918-9823

  5. RASopathies and lymphatic malformation

    青木洋子, 野澤明史, 小関道夫, 阿部太紀, 新堀哲也

    リンパ学　47　(Supplement)　2024

    ISSN： 0910-4186

  6. Mutation related to MECOM-associated syndrome reduces hematopoietic stem and progenitor cells in mice

    新堀哲也, 永井康貴, 武藤哲彦, 林慶和, 阿部太紀, 五十嵐和彦, 青木洋子

    日本小児科学会雑誌　128　(2)　2024

    ISSN： 0001-6543

  7. LZTR1欠損はEMT誘導とKLHL12依存的なコラーゲン分泌を制御することで腫瘍増殖と腫瘍転移を促進する

    阿部 太紀, 菅野 新一郎, 新堀 哲也, 寺尾 美穂, 高田 修治, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　96回　[1P-666]　2023/10

    Publisher: (公社)日本生化学会

  8. 先天異常症候群のライフステージ全体の自然歴と合併症の把握:Reverse phenotypingを包含したアプローチ RAS信号伝達系に関連する先天異常症候群等,東北地区成育医療施設としての支援機能。コステロ症候群・CFC症候群,先天異常症候群

    青木洋子, 新堀哲也, 阿部太紀, 永井康貴

    先天異常症候群のライフステージ全体の自然歴と合併症の把握:Reverse Phenotypingを包含したアプローチ 令和4年度 総括・分担研究報告書(Web)　2023

  9. Molecular pathogenesis in two cases of IMAGE-I syndrome with novel POLE mutations

    中野智太, 森谷邦彦, 菊池敦生, 新妻秀剛, 笹原洋二, 舟山亮, 中山啓子, 城田松之, 新堀哲也, 青木洋子, 呉繁夫

    日本免疫不全・自己炎症学会雑誌(Web)　2　(2)　2023

    ISSN： 2435-7693

  10. LZTR1機能不全によるがん原遺伝子産物RASの異常蓄積と腫瘍増殖の亢進

    阿部 太紀, 森崎 佳歩, 新堀 哲也, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　95回　3P-308　2022/11

    Publisher: (公社)日本生化学会

  11. 57歳時に確定診断に至った2型コラーゲン異常症の一例

    津幡 真理, 新堀 哲也, 堅田 有宇, 永井 康貴, 野澤 明史, 城之前 翼, 後藤 悠輔, 川村 真亜子, 要 匡, 青木 洋子

    日本遺伝カウンセリング学会誌　43　(2)　82-82　2022/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  12. 幅広い臨床症状を呈したMECOM遺伝子変異を同定した2家系

    新堀 哲也, 田野島 玲大, 笹原 洋二, 佐藤 篤, 入江 正寛, 南條 由佳, 舟山 亮, 城田 松之, 阿部 太紀, 奥山 祐子, 石井 直人, 中山 啓子, 呉 繁夫, 今泉 益栄, 青木 洋子

    日本小児科学会雑誌　126　(2)　230-230　2022/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  13. 幅広い臨床症状を呈したMECOM遺伝子変異を同定した2家系

    新堀 哲也, 田野島 玲大, 笹原 洋二, 佐藤 篤, 入江 正寛, 南條 由佳, 舟山 亮, 城田 松之, 阿部 太紀, 奥山 祐子, 石井 直人, 中山 啓子, 呉 繁夫, 今泉 益栄, 青木 洋子

    日本小児科学会雑誌　126　(2)　230-230　2022/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  14. 先天異常症候群のライフステージ全体の自然歴と合併症の把握:Reverse phenotypingを包含したアプローチ RAS信号伝達系に関連する先天異常症候群等,東北地区成育医療施設としての支援機能。コステロ症候群・CFC症候群,先天異常症候群

    青木洋子, 新堀哲也, 阿部太紀, 永井康貴

    先天異常症候群のライフステージ全体の自然歴と合併症の把握:Reverse Phenotypingを包含したアプローチ 令和3年度 総括・分担研究報告書(Web)　2022

  15. ユビキチンE3リガーゼ基質アダプターLZTR1はRASプロテオスタシスと腫瘍増殖を制御する

    阿部太紀, 森崎佳歩, 新堀哲也, 青木洋子

    日本人類遺伝学会大会プログラム・抄録集　67th (CD-ROM)　2022

  16. 骨髄不全や四肢の先天異常を呈するMECOM異常症での表現型に関連しうるメカニズム

    新堀哲也, 永井康貴, 阿部太紀, 青木洋子

    日本人類遺伝学会大会プログラム・抄録集　67th (CD-ROM)　2022

  17. Somatic RASopathies:リンパ管腫症・Gorham病の原因検索

    青木洋子, 野澤明史, 野澤明史, 阿部太紀, 新堀哲也, 小関道夫

    日本遺伝子診療学会大会プログラム・抄録集　29th　2022

  18. 日本人一般集団に高頻度で見出され病的バリアントであると判断しがたいジスフェルリン遺伝子のc.3725G>A(p.R1242H)の神経筋疾患での頻度

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 小野 洋也, 戸恒 智子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究　8　41-41　2021/11

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  19. Identification of Somatic Activating Variants of the RAS/MAPK Pathway in Patients with Complex Lymphatic Anomalies

    Akifumi Nozawa, Yoko Aoki, Taiki Abe, Tetsuya Niihori, Michio Ozeki, Shiho Yasue, Saori Endo, Hidenori Ohnishi

    PEDIATRIC BLOOD & CANCER　68　2021/11

    ISSN： 1545-5009

    eISSN： 1545-5017

  20. LSS欠損症における組織特異的モデルマウスを用いた代謝および病理プロファイル

    和田 陽一, 菊池 敦生, 加賀 元宗, 清水 直紀, 伊藤 隼哉, 新堀 哲也, 佐藤 孝太, 中澤 徹, 中山 啓子, 青木 洋子, 仲川 清隆, 呉 繁夫

    日本先天代謝異常学会雑誌　37　126-126　2021/09

    Publisher: (一社)日本先天代謝異常学会

    ISSN： 0912-0122

  21. 臨床病型が大きく異なりFUS遺伝子変異のmosaicismが示唆された家族性ALS母子例

    久原 真, 西山 亜由美, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 石川 亜貴, 櫻井 晃洋, 元池 育子, 青木 正志, 青木 洋子, 下濱 俊

    臨床神経学　61　(Suppl.)　S293-S293　2021/09

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  22. 当院のがんゲノム医療における認定遺伝カウンセラーの役割

    川村 真亜子, 津幡 真理, 杉山 育子, 小峰 啓吾, 新堀 哲也, 城田 英和, 青木 洋子, 石岡 千加史

    日本遺伝カウンセリング学会誌　42　(2)　71-71　2021/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  23. Noonan症候群類縁疾患を有する子どもの療養生活及び養育者の心理社会的側面に関する実態調査

    小野 智愛, 新堀 哲也, 深見 真紀, 黒澤 健司, 大橋 博文, 岡本 伸彦, 水野 誠司, 緒方 勤, 松原 洋一, 津幡 真理, 川村 真亜子, 川目 裕, 青木 洋子

    日本遺伝カウンセリング学会誌　42　(2)　55-55　2021/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  24. Learning 難治性疾患(難病)を学ぶ RASopathies:Noonan症候群類縁疾患

    青木 洋子

    遺伝子医学　11　(2)　98-103　2021/04

    Publisher: (株)メディカルドゥ

    ISSN： 1343-0971

  25. HRAS G12V変異による最重症のCostello症候群

    藤井 隆, 須藤 陽介, 佐々木 綾子, 永井 康貴, 青木 洋子, 三井 哲夫

    日本小児科学会雑誌　125　(3)　461-466　2021/03

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  26. Costello症候群モデルマウスにおけるアレルゲンによる皮膚炎の誘発と病態メカニズムの解明

    堅田 有宇, 井上 晋一, 浅尾 敦子, 小林 周平, 照井 仁, 井上 彩, 阿部 太紀, 新堀 哲也, 相場 節也, 石井 直人, 呉 繁夫, 青木 洋子

    日本小児科学会雑誌　125　(2)　292-292　2021/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  27. 【新型コロナウイルス関連特集】教育面(実践報告2) 各遺伝カウンセラー養成コースの取り組み 2020年度の遺伝カウンセリングコース実践記録

    青木 洋子

    日本遺伝カウンセリング学会誌　41　(4)　193-196　2021/02

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  28. HRAS遺伝子内重複患者の分子学的解析と臨床症状

    永井康貴, 新堀哲也, 岡本伸彦, 近藤朱音, 須賀健一, 大平智子, 早渕康信, 本間友佳子, 中川竜二, 井福俊允, 阿部太紀, 水口剛, 松本直通, 青木洋子

    日本人類遺伝学会大会プログラム・抄録集　66th (CD-ROM)　2021

  29. 先天異常症候群のライフステージ全体の自然歴と合併症の把握:Reverse phenotypingを包含したアプローチ「RAS信号伝達系に関連する先天異常症候群等,東北地区成育医療施設としての支援機能:コステロ症候群・CFC症候群,先天異常症候群」

    青木洋子, 松原洋一, 緒方勤, 黒澤健司, 岡本伸彦, 大橋博文, 水野誠司, 新堀哲也, 川目裕, 阿部太紀, 永井康貴

    先天異常症候群のライフステージ全体の自然歴と合併症の把握:Reverse Phenotypingを包合したアプローチ 令和2年度 総括・分担研究報告書(Web)　2021

  30. 多系統蛋白質症(MSP)患者の全国実態調査と診療体制構築に関する研究 HNRNPA1変異を伴う多系統蛋白質症(MSP3型)新規家系の同定

    青木正志, 割田仁, 井泉瑠美子, 井泉瑠美子, 池田謙輔, 鈴木直輝, 高橋俊明, 竪山真規, 西山亜由美, 城田松之, 舟山亮, 中山啓子, 三橋里美, 西野一三, 新堀哲也, 青木洋子

    多系統蛋白質症(MSP)患者の全国実態調査と診療体制構築に関する研究 令和2年度 総括・分担研究報告書(Web)　2021

  31. 複雑型脈管異常におけるRAS遺伝子変異の同定

    野澤明史, 野澤明史, 青木洋子, 阿部太紀, 新堀哲也, 小関道夫, 安江志保, 遠渡沙緒理, 大西秀典

    日本血管腫血管奇形学会学術集会プログラム・抄録集　17th　2021

  32. 日本人一般集団に高頻度で見出されるジスフェルリン遺伝子のc.3725G>A(p.R1242H)バリアントの臨床像の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 戸恒 智子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究　7　65-65　2021/01

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  33. 日本人一般集団に高頻度で見出されるジスフェルリン遺伝子のc.3725G>A(p.R1242H)バリアントの臨床像の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 戸恒 智子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究　7　65-65　2021/01

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  34. 異なる臨床病型を呈し母にFUS遺伝子変異のmosaicismが示唆された家族性ALSの親子例

    久原 真, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 石川 亜貴, 櫻井 晃洋, 西山 亜由美, 元池 育子, 青木 正志, 青木 洋子, 下濱 俊

    臨床神経学　61　(1)　55-55　2021/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  35. 日本人一般集団に高頻度で見出されるdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　60　(Suppl.)　S387-S387　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  36. ジスフェルリン異常症209家系の臨床遺伝学的特徴

    井泉 瑠美子, 高橋 俊明, 鈴木 直輝, 新堀 哲也, 小野 洋也, 中村 尚子, 堅田 慎一, 加藤 昌昭, 割田 仁, 竪山 真規, 青木 洋子, 青木 正志

    臨床神経学　60　(Suppl.)　S387-S387　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  37. がん原遺伝子産物RASの恒常性維持機構の解明

    阿部 太紀, 梅木 郁美, 菅野 新一郎, 井上 晋一, 新堀 哲也, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　93回　[P-190]　2020/09

    Publisher: (公社)日本生化学会

  38. 成熟神経細胞特異的RAS/MAPK症候群モデル動物の表現型解析

    森谷 晃, 井上 晋一, 青木 洋子, 大西 浩史

    The Kitakanto Medical Journal　70　(3)　296-296　2020/08

    Publisher: 北関東医学会

    ISSN： 1343-2826

    eISSN： 1881-1191

  39. 【遺伝情報と遺伝カウンセリング】Noonan症候群類縁疾患の遺伝学的検査と遺伝カウンセリング

    青木 洋子

    小児内科　52　(8)　1104-1105　2020/08

    Publisher: (株)東京医学社

    ISSN： 0385-6305

  40. 【循環器症候群(第3版)-その他の循環器疾患を含めて-】染色体異常・奇形症候群に見られる心・血管異常 RAS/MAPK症候群(Noonan症候群、Costello症候群、CFC症候群)

    青木 洋子

    日本臨床　別冊　(循環器症候群IV)　386-390　2020/03

    Publisher: (株)日本臨床社

    ISSN： 0047-1852

  41. BRCA1/2遺伝学的検査を受けた未発症血縁者に対する遺伝カウンセリング

    津幡真理, 新堀哲也, 新堀哲也, 永井康貴, 井上彩, 野澤明史, 多田寛, 原田成美, 島田宗昭, 石田孝宣, 青木洋子, 青木洋子

    日本遺伝性腫瘍学会学術集会プログラム・抄録集　26th　2020

  42. 初診から10年後にDanon病と診断された男性とその母への遺伝カウンセリング

    津幡真理, 新堀哲也, 新堀哲也, 堅田有宇, 永井康貴, 井上彩, 鈴木秀明, 青木洋子, 青木洋子

    日本遺伝子診療学会大会プログラム・抄録集　27th　2020

  43. 複雑型脈管異常におけるRAS遺伝子変異の同定

    野澤明史, 野澤明史, 青木洋子, 新堀哲也, 阿部太紀, 小関道夫, 青木洋子

    日本人類遺伝学会大会プログラム・抄録集　65th (CD-ROM)　2020

  44. がん遺伝子パネル検査の時代を迎えて 治療に直結した2例の報告

    新妻 秀剛, 片山 紗乙莉, 森谷 邦彦, 渡辺 祐子, 入江 正寛, 力石 健, 新堀 哲也, 青木 洋子, 末原 義之, 加藤 俊介, 笹原 洋二, 呉 繁夫

    日本小児科学会雑誌　124　(1)　99-99　2020/01

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  45. 指定難病最前線(Volume97) コステロ症候群

    青木 洋子

    新薬と臨牀　68　(12)　1573-1576　2019/12

    Publisher: (株)医薬情報研究所

    ISSN： 0559-8672

  46. 日本人dysferlin遺伝子解析で見出されたバリアントの一般頻度による病的意義の推定

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　59　(Suppl.)　S257-S257　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  47. RASサブファミリータンパク質RIT1ノックインマウスにおける心疾患病態解析

    井上 晋一, 高原 真吾, 宮川 幸子[富田], 松浦 勝久, 中嶌 八隅, 新堀 哲也, 松原 洋一, 齋木 佳克, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　92回　[1T02a-01]　2019/09

    Publisher: (公社)日本生化学会

  48. GALMの両アレル性変異はガラクトース血症IV型を呈する Peer-reviewed

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 岩澤 伸哉, 竹澤 祐介, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲哉, 小原 收, 青木 洋子, 深尾 敏幸, 呉 繁夫

    日本先天代謝異常学会雑誌　35　114-114　2019/09

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  49. RASサブファミリータンパク質RIT1ノックインマウスにおける心疾患病態解析

    井上 晋一, 高原 真吾, 宮川 幸子[富田], 松浦 勝久, 中嶌 八隅, 新堀 哲也, 松原 洋一, 齋木 佳克, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　92回　[1T02a-01]　2019/09

    Publisher: (公社)日本生化学会

  50. NGSを用いた希少遺伝性疾患の研究やその医療への応用

    青木 洋子

    日本染色体遺伝子検査学会雑誌　37　(2)　21-21　2019/09

    Publisher: 日本染色体遺伝子検査学会

    ISSN： 1884-3026

  51. 日本人dysferlin遺伝子解析で見出されたバリアントのデータベースによる検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集　5回　172-172　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  52. 日本人dysferlin遺伝子解析で見出されたバリアントのデータベースによる検討 Peer-reviewed

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集　5回　172-172　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  53. Noonan症候群類縁疾患の網羅的解析とLZTR1の機能解明 Peer-reviewed

    青木 洋子, 梅木 郁美, 阿部 太紀, 岡本 伸彦, 水野 誠司, 黒澤 健司, 長崎 啓祐, 吉田 真, 大橋 博文, 井上 晋一, 松原 洋一, 藤原 幾磨, 呉 繁夫, 新堀 哲也

    日本遺伝カウンセリング学会誌　40　(2)　85-85　2019/07

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  54. 大規模ゲノムコホート調査におけるBRCA1/2遺伝子の病的バリアント保持者への遺伝情報回付に関する課題

    濱中 洋平, 石田 孝宣, 布施 昇男, 川目 裕, 山口 由美, 安田 純, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 青木 洋子, 長神 風二, 八重樫 伸生, 木下 賢吾, 呉 繁夫, 山本 雅之

    日本乳癌学会総会プログラム抄録集　27回　332-332　2019/07

    Publisher: (一社)日本乳癌学会

  55. Noonan症候群類縁疾患の網羅的解析とLZTR1の機能解明

    青木 洋子, 梅木 郁美, 阿部 太紀, 岡本 伸彦, 水野 誠司, 黒澤 健司, 長崎 啓祐, 吉田 真, 大橋 博文, 井上 晋一, 松原 洋一, 藤原 幾磨, 呉 繁夫, 新堀 哲也

    日本遺伝カウンセリング学会誌　40　(2)　85-85　2019/07

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  56. 幼少期に網膜血管腫から診断されたvon Hippel-Lindau病の1例

    津幡 真理, 永井 康貴, 堅田 有宇, 井上 彩, 新堀 哲也, 青木 洋子

    日本遺伝カウンセリング学会誌　40　(2)　149-149　2019/07

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  57. 【小児循環器領域の生涯包括遺伝医療】疾患各論 Noonan症候群の遺伝学

    青木 洋子

    小児科診療　82　(7)　907-911　2019/07

    Publisher: (株)診断と治療社

    ISSN： 0386-9806

  58. 満期産脳性麻痺群の網羅的遺伝学的解析 17例中9例で候補遺伝子変異を同定

    竹澤 祐介, 菊池 敦生, 萩野谷 和裕, 新堀 哲也, 沼田 有里佳, 松, 乾 健彦, 山村 菜絵子, 宮林 拓矢, 安西 真衣, 鈴木 智, 室本, 大久保 幸宗, 遠藤 若葉, 冨樫 紀子, 小林 康子, 大沼 晃, 舟山 亮, 城田 松之, 中山 啓子, 青木 洋子, 呉 繁夫

    日本小児科学会雑誌　123　(6)　1069-1070　2019/06

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  59. 【指定難病ペディア2019】個別の指定難病 染色体・遺伝子関連 ヌーナン症候群[指定難病195]

    青木 洋子

    日本医師会雑誌　148　(特別1)　S302-S303　2019/06

    Publisher: (公社)日本医師会

    ISSN： 0021-4493

  60. 大頭症、軽度運動発達遅滞、白質信号異常を呈し、PTEN遺伝子変異を認めた男児例

    黒子 由梨香, 山本 薫, 横山 美奈, 代田 惇朗, 平林 真介, 真部 淳, 荻原 正明, 草川 功, 青木 洋子, 小崎 里華

    脳と発達　51　(Suppl.)　S359-S359　2019/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

  61. Noonan症候群の原因遺伝子LZTR1 臨床的特徴と結合タンパクRAF1/PPP1CBの同定 Peer-reviewed

    梅木 郁美, 新堀 哲也, 阿部 太紀, 長崎 啓祐, 井上 晋一, 藤原 幾磨, 呉 繁夫, 青木 洋子

    日本内分泌学会雑誌　95　(1)　382-382　2019/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  62. Noonan症候群の原因遺伝子LZTR1 臨床的特徴と結合タンパクRAF1/PPP1CBの同定

    梅木 郁美, 新堀 哲也, 阿部 太紀, 長崎 啓祐, 井上 晋一, 藤原 幾磨, 呉 繁夫, 青木 洋子

    日本内分泌学会雑誌　95　(1)　382-382　2019/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

  63. GALMの両アレル性変異はガラクトース血症IV型を呈する(Blallelic GALM pathogenic variants cause a novel type of galactosemia)

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 竹澤 祐介, 岩澤 伸哉, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲也, 小原 収, 青木 洋子, 小柴 生造, 深尾 敏幸, 呉 繁夫

    日本小児科学会雑誌　123　(2)　280-280　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  64. 6つのネフローゼ遺伝子変異が描く治療可能な病態パスウェイ

    菊池 敦生, 工藤 宏紀, 新堀 哲也, 熊谷 直憲, 貝藤 裕史, 野津 寛大, 田中 亮二郎, 濱平 陽史, 小林 靖子, 滝沢 琢己, 青木 洋子, 飯島 一誠, 呉 繁夫

    日本小児科学会雑誌　123　(2)　283-283　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  65. 新規コステロ症候群モデルマウスを用いたエネルギー代謝変化の病態解明

    大場 大樹, 中嶌 八隅, 新堀 哲也, 山口 清次, 松原 洋一, 青木 洋子, 井上 晋一, 宮川 幸子

    日本小児科学会雑誌　123　(2)　284-284　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  66. 6つのネフローゼ遺伝子変異が描く治療可能な病態パスウェイ

    菊池 敦生, 工藤 宏紀, 新堀 哲也, 熊谷 直憲, 貝藤 裕史, 野津 寛大, 田中 亮二郎, 濱平 陽史, 小林 靖子, 滝沢 琢己, 青木 洋子, 飯島 一誠, 呉 繁夫

    日本小児科学会雑誌　123　(2)　283-283　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  67. GALMの両アレル性変異はガラクトース血症IV型を呈する(Blallelic GALM pathogenic variants cause a novel type of galactosemia)

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 竹澤 祐介, 岩澤 伸哉, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲也, 小原 収, 青木 洋子, 小柴 生造, 深尾 敏幸, 呉 繁夫

    日本小児科学会雑誌　123　(2)　280-280　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  68. 新規コステロ症候群モデルマウスを用いたエネルギー代謝変化の病態解明

    大場 大樹, 中嶌 八隅, 新堀 哲也, 山口 清次, 松原 洋一, 青木 洋子, 井上 晋一, 宮川 幸子

    日本小児科学会雑誌　123　(2)　284-284　2019/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  69. Noonan症候群原因遺伝子産物LZTR1によるRAS分解促進機構の解明

    阿部太紀, 梅木郁美, 菅野新一郎, 井上晋一, 新堀哲也, 青木洋子

    日本分子生物学会年会プログラム・要旨集(Web)　42nd　2019

  70. Kaposiform Lymphangiomatosis Caused by a Somatic Mutation in the Neuroblastoma RAS Viral Oncogene Homolog Gene (NRAS)

    Michio Ozeki, Akifumi Nozawa, Shiho Yasue, Saori Endo, Tetsuya Niihori, Yoko Aoki, Toshiyuki Fukao

    PEDIATRIC BLOOD & CANCER　65　S25-S25　2018/11

    ISSN： 1545-5009

    eISSN： 1545-5017

  71. 日本人dysferlin遺伝子解析で見出された全バリアントの検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 倉島 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 洋子, 青木 正志

    国立病院総合医学会講演抄録集　72回　737-737　2018/11

    Publisher: 国立病院総合医学会

  72. MECOM(EVI1)遺伝子変異による無巨核球性血小板減少症を伴う橈骨尺骨融合症

    今泉 益栄, 新堀 哲也, 笹原 洋二, 内山 芽里, 入江 正寛, 佐藤 篤, 南條 由佳, 橋井 佳子, 金子 隆, 呉 繁夫, 青木 洋子

    日本小児血液・がん学会雑誌　55　(3)　335-335　2018/10

    Publisher: (一社)日本小児血液・がん学会

    ISSN： 2187-011X

    eISSN： 2189-5384

  73. Hras G12Sノックインマウスは食餌誘導性肥満の抑制および肝エネルギー代謝異常を示す

    井上 晋一, 大場 大樹, 宮川 幸子, 田, 中嶌 八隅, 新堀 哲也, 山口 清次, 松原 洋一, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　91回　[2T14a-10(2P　2018/09

    Publisher: (公社)日本生化学会

  74. 次世代シークエンサーを用いたジスフェルリン異常症の遺伝子解析

    井泉瑠美子, 新堀哲也, 高橋俊明, 鈴木直輝, 竪山真規, 小野洋也, 加藤昌昭, 割田仁, 青木洋子, 青木正志

    日本筋学会学術集会プログラム・抄録集　4th　191-191　2018/08/01

    Publisher: 日本筋学会

    ISSN： 2433-975X

  75. 次世代シークエンサーを用いたジスフェルリン異常症の遺伝子解析

    井泉 瑠美子, 新堀 哲也, 高橋 俊明, 鈴木 直輝, 竪山 真規, 小野 洋也, 加藤 昌昭, 割田 仁, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集　4回　191-191　2018/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  76. Noonan症候群の遺伝学的検査に関する遺伝カウンセリング

    津幡 真理, 梅木 郁美, 井上 彩, 堅田 有宇, 永井 康貴, 福與 なおみ, 新堀 哲也, 川目 裕, 青木 洋子

    日本遺伝カウンセリング学会誌　39　(2)　102-102　2018/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  77. 日本人骨形成不全症患者の遺伝的背景の解明とアレンドロネート注治療の有用性の検討

    菅野 潤子, 川嶋 明香, 島 彦仁, 曽木 千純, 梅木 郁美, 鈴木 大, 上村 美季, 新堀 哲也, 青木 洋子, 藤原 幾磨, 呉 繁夫

    日本内分泌学会雑誌　94　(1)　321-321　2018/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  78. 日本人骨形成不全症患者の遺伝的背景の解明とアレンドロネート注治療の有用性の検討

    菅野 潤子, 川嶋 明香, 島 彦仁, 曽木 千純, 梅木 郁美, 鈴木 大, 上村 美季, 新堀 哲也, 青木 洋子, 藤原 幾磨, 呉 繁夫

    日本小児科学会雑誌　122　(2)　236-236　2018/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  79. RASopathiesに対する網羅的遺伝子解析

    梅木 郁美, 新堀 哲也, 岡本 伸彦, 水野 誠司, 黒沢 健司, 長崎 啓祐, 吉田 真, 松原 洋一, 藤原 幾磨, 呉 繁夫, 青木 洋子, 阿部 太紀, 井上 晋一

    日本小児科学会雑誌　122　(2)　229-229　2018/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  80. BRAF変異により多発性黒子を伴うNoonan症候群と診断した13歳女児例

    林 仁美, 鶴澤 礼実, 坂口 崇, 山崎 靖人, 佐々木 聡子, 小川 厚, 青木 洋子

    日本小児科学会雑誌　122　(2)　459-459　2018/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  81. Mouse model of Costello syndrome: impaired hepatic energy homeostasis and resistance to high-fat diet induced obesity in mice with a heterozygous Hras G12S mutation

    Daiju Oba, Shin-ichi Inoue, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Tetsuya Niihori, Seiji Yamaguchi, Yoichi Matsubara, Yoko Aoki

    American Society of Human Genetics　2018

  82. がん原遺伝子Brafの活性化はマウス食道の拡張と前胃上皮の過増殖をもたらす

    井上 晋一, 高原 真吾, 吉川 雄朗, 新堀 哲也, 谷内 一彦, 松原 洋一, 青木 洋子

    生命科学系学会合同年次大会　2017年度　[1LBA-090]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  83. 次世代シークエンサーを用いたジスフェルリン異常症の遺伝子解析

    井泉瑠美子, 新堀哲也, 高橋俊明, 八木沼智香子, 鈴木直輝, 島倉奈緒子, 竪山真規, 竪山真規, 小野洋也, 加藤昌昭, 割田仁, 武田篤, 青木洋子, 青木正志

    筋ジストロフィー医療研究　4　86-86　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  84. 日本人骨形成不全症の遺伝的背景とアレンドロネート治療の有用性

    菅野 潤子, 川嶋 明香, 島 彦仁, 曽木 千純, 梅木 郁美, 鈴木 大, 上村 美季, 新堀 哲也, 青木 洋子, 呉 繁夫, 藤原 幾磨

    日本内分泌学会雑誌　93　(2)　543-543　2017/10

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  85. COL4A1遺伝子変異は、てんかん外科の禁忌ではない(The patients with mutations in COL4A1 may not be absolute contraindication for epilepsy surgery)

    福與 なおみ, 岩崎 真樹, 菊池 敦生, 萩野谷 和裕, 青木 洋子, 新堀 哲也, 呉 繁夫

    てんかん研究　35　(2)　432-432　2017/09

    Publisher: (一社)日本てんかん学会

    ISSN： 0912-0890

    eISSN： 1347-5509

  86. 不均衡型転座を18トリソミーと考えていた両親に対する遺伝カウンセリング

    津幡 真理, 福與 なおみ, 新堀 哲也, 青木 洋子

    日本遺伝カウンセリング学会誌　38　(2)　117-117　2017/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  87. 機能的半球離断が奏功した、COL4A1遺伝子異常を持つてんかん性脳症の1例(A case with epileptic encephalopathy and COL4A1 mutation, medicated by functional hemispherectomy)

    福與 なおみ, 菊池 敦生, 岩崎 真樹, 佐藤 優子, 久保田 由紀, 小林 朋子, 中山 東城, 萩野谷 和裕, 新堀 哲也, 青木 洋子, 呉 繁夫

    脳と発達　49　(Suppl.)　S301-S301　2017/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  88. 【次世代遺伝子解析技術が血栓止血にもたらした新知見】 無巨核球性血小板減少症を伴う橈尺骨癒合症の原因遺伝子の同定

    新堀 哲也, 青木 洋子

    日本血栓止血学会誌　28　(1)　16-23　2017/02

    Publisher: (一社)日本血栓止血学会

    ISSN： 0915-7441

  89. MECOM(EVI)遺伝子変異は無巨核球性血小板減少症を伴う橈尺骨癒合症を引き起こす

    新堀 哲也, 内山 芽里, 笹原 洋二, 入江 正寛, 佐藤 篤, 南條 由佳, 呉 繁夫, 松原 洋一, 今泉 益栄, 青木 洋子, 金子 隆, 橋井 佳子, 舟山 亮, 長嶋 剛史, 井上 晋一, 中山 啓子, 大薗 恵一

    日本小児科学会雑誌　121　(2)　300-300　2017/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  90. CFC症候群の成獣型モデルマウスの作製と解析

    守谷 充司, 井上 晋一, 大場 大樹, 宮川 幸子, 田, 中嶌 八隅, 新堀 哲也, 呉 繁夫, 松原 洋一, 青木 洋子

    日本小児科学会雑誌　121　(2)　301-301　2017/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  91. 筋ジストロフィー関連疾患の基盤的診断・治療開発研究 Dysferlinopathyおよび類似疾患の次世代シークエンサーを用いた診断および結合蛋白に注目した病態研究

    青木正志, 小野洋也, 井泉瑠美子, 鈴木直輝, 菅野新一郎, 高橋俊明, 割田仁, 加藤昌昭, 西山亜由美, 島倉奈緒子, 舟山亮, 中山啓子, 新堀哲也, 青木洋子, 三宅克也, 三宅克也

    筋ジストロフィー関連疾患の基盤的診断・治療開発研究 平成26-28年度 総括研究報告書　18‐20　2017

  92. 難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 日本人ジスフェルリン異常症の遺伝子検索への次世代シークエンサーの導入

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 新堀哲也, 片山望, 齋藤京之, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木洋子, 三橋里美, 西野一三

    難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 平成28年度 総括・分担研究報告書(Web)　201610042A0007 (WEB ONLY)　2017

  93. 多系統プロテイノパチー連鎖性hnRNPA1変異に起因する孤立性封入体ミオパチー(Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation)

    井泉 瑠美子, 割田 仁, 新堀 哲也, 高橋 俊明, 竪山 真規, 鈴木 直輝, 西山 亜由美, 城田 松之, 舟山 亮, 中山 啓子, 三橋 里美, 西野 一三, 青木 洋子, 青木 正志

    臨床神経学　56　(Suppl.)　S280-S280　2016/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  94. 【先天異常症候群の新しい展開】 日本が貢献した先天異常症候群 RASopathies:Noonan症候群類縁疾患

    青木 洋子, 新堀 哲也, 井上 晋一, 松原 洋一

    小児科診療　79　(12)　1777-1781　2016/12

    Publisher: (株)診断と治療社

    ISSN： 0386-9806

  95. EVI1遺伝子変異が引き起こす無巨核球性血小板減少症を伴う橈骨尺骨融合症(遺伝性骨髄不全症候群の一型)

    今泉益栄, 新堀哲也, 内山芽里, 内山芽里, 笹原洋二, 金子隆, 橋井佳子, 入江正寛, 入江正寛, 佐藤篤, 南條由佳, 船山亮, 長嶋剛史, 井上晋一, 中山啓子, 大薗恵一, 呉繁夫, 松原洋一, 青木洋子

    日本小児整形外科学会雑誌　25　(3)　S23　2016/11/01

    ISSN： 0917-6950

  96. 新規原因遺伝子MECOM(EVI1)変異をもつ橈尺骨癒合を伴う無巨核球性血小板減少症への造血幹細胞移植3症例の検討(The issues of three cases of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia, harboring novel MECOM(EVI1) mutations in the HSCT setting)

    入江 正寛, 今泉 益栄, 内山 芽里, 南條 由佳, 新堀 哲也, 佐藤 篤, 橋井 佳子, 金子 隆, 笹原 洋二, 青木 洋子, 呉 繁夫

    日本小児血液・がん学会雑誌　53　(4)　261-261　2016/11

    Publisher: (一社)日本小児血液・がん学会

    ISSN： 2187-011X

    eISSN： 2189-5384

  97. ヌーナン症候群と類縁疾患の遺伝子診断体制の確立とその病態解明

    青木洋子, 梅木郁美, 大場大樹, 西山亜由美, 高原真吾, 矢尾板全子, 井上晋一, 松原洋一, 新堀哲也

    日本遺伝子診療学会大会プログラム・抄録集　23rd　77　2016/10/06

  98. ヌーナン症候群類縁疾患における遺伝子診断の現況

    矢尾板 全子, 大場 大樹, 梅木 郁美, 井上 晋一, 呉 繁夫, 新堀 哲也, 青木 洋子

    日本小児科学会雑誌　120　(10)　1552-1553　2016/10

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  99. MUTATIONS IN MECOM, ENCODING ONCOPROTEIN EVI1, CAUSE AMEGAKARYOCYTIC THROMBOCYTOPENIA WITH RADIOULNAR SYNOSTOSIS, AN INHERITED BONE MARROW FAILURE SYNDROME

    Masue Imaizumi, Tetsuya Niihori, Meri Ouchi-Uchiyama, Yoji Sasahara, Takashi Kaneko, Yoshiko Hashii, Masahiro Irie, Atsushi Sato, Yuka Saito-Nanjo, Ryo Funayama, Takeshi Nagashima, Shin-ichi Inoue, Keiko Nakayama, Keiichi Ozono, Shigeo Kure, Yoichi Matsubara, Yoko Aoki

    EXPERIMENTAL HEMATOLOGY　44　(9)　S44-S45　2016/09

    DOI： 10.1016/j.exphem.2016.06.052 　

    ISSN： 0301-472X

    eISSN： 1873-2399

  100. A NOVEL GENODERMATOSIS SYNDROME INDUCED BY SOMATIC BRAF V600E MOSAICISM, COMPRISING CONGENITAL ANAPLASTIC ASTROCYTOMA AND LINEAR SYRINGOCYSTADENOMA PAPILLIFERUM

    Yuko Watanabe, Hidetaka Niizuma, Kousuke Shido, Tetsuya Niihori, Takeshi Rikiishi, Yukihiko Sonoda, Yoko Aoki, Setsuya Aiba, Yoji Sasahara, Shigeo Kure

    NEURO-ONCOLOGY　18　48-48　2016/06

    ISSN： 1522-8517

    eISSN： 1523-5866

  101. ウエスト症候群を呈した19p13.2欠失患者の臨床経過(Long-term clinical feature of West syndrome with a de novo 19p13.2 deletion: a case report)

    福與 なおみ, 菊池 敦生, 廣瀬 三恵子, 横山 浩之, 萩野谷 和裕, 市野井 那津子, 佐藤 亮, 新堀 哲也, 青木 洋子, 呉 繁夫

    脳と発達　48　(Suppl.)　S412-S412　2016/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

  102. 診断から5年後にご両親が遺伝カウンセリングを希望したEmanuel症候群の一例

    津幡真理, 福與なおみ, 新堀哲也, 青木洋子

    日本遺伝カウンセリング学会誌　37　(1)　65　2016/03/11

    ISSN： 1347-9628

  103. 【膵疾患の分子病態】 次世代シークエンサーを用いた膵炎関連遺伝子の網羅的解析

    中野 絵里子, 正宗 淳, 新堀 哲也, 粂 潔, 青木 洋子, 下瀬川 徹

    膵臓　31　(1)　54-62　2016/02

    Publisher: 日本膵臓学会

    DOI： 10.2958/suizo.31.54 　

    ISSN： 0913-0071

  104. ヌーナン症候群と類縁疾患の遺伝子診断体制の確立とその病態解明

    青木洋子, 矢尾板全子, 梅木郁美, 大場大樹, 井上晋一, 松原洋一, 新堀哲也

    日本小児科学会雑誌　120　(2)　211　2016/02/01

    ISSN： 0001-6543

  105. 新しいゲノム解析技術による小児疾患研究のブレイクスルー もやもや病の遺伝学的背景の解明

    呉 繁夫, 鎌田 文顕, 阿部 裕, 菊池 敦生, 青木 洋子, 松原 洋一, 宮武 聡子, 松本 直通

    日本小児科学会雑誌　120　(2)　177-177　2016/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  106. ヌーナン症候群類縁疾患におけるRIT1遺伝子解析と臨床的特徴の検討

    矢尾板 全子, 大場 大樹, 梅木 郁美, 水野 誠司, 岡本 伸彦, 井上 晋一, 松原 洋一, 呉 繁夫, 新堀 哲也, 青木 洋子

    日本小児科学会雑誌　120　(2)　277-277　2016/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  107. PPIB遺伝子に新規のミスセンス変異をホモ接合性に同定した骨形成不全症の一例

    菅野 潤子, 川嶋 さやか, 曽木 千純, 上村 美季, 新堀 哲也, 青木 洋子, 呉 繁夫, 藤原 幾磨

    日本小児科学会雑誌　120　(2)　298-298　2016/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  108. 難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 日本人ジスフェルリン異常症の遺伝子検索への次世代シークエンサーの導入

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 新堀哲也, 片山望, 齋藤京之, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木洋子, 三橋里美, 西野一三

    難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 平成27年度 総括・分担研究報告書　15‐16　2016

  109. Dysferlin遺伝子診断への次世代シークエンサーの活用と日本人の遺伝子変異の特徴

    高橋俊明, 井泉瑠美子, 八木沼智香子, 加藤昌昭, 島倉奈緒子, 鈴木直輝, 新堀哲也, 青木洋子, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 武田篤, 青木正志

    日本神経学会学術大会プログラム・抄録集　55　(Suppl.)　S390-S390　2015/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  110. 稀少疾患の分子病態メカニズム RASopathiesの新規原因検索とモデルマウス作製

    青木 洋子, 井上 晋一, 新堀 哲也, 松原 洋一

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[1W5-p　2015/12

    Publisher: (公社)日本生化学会

  111. がん原遺伝子BRAFの機能獲得性変異は先天性異常を引き起こす

    井上 晋一, 守谷 充司, 宮川 幸子, 田, 中嶌 八隅, 大場 大樹, 新堀 哲也, 橋 美里, 大西 浩史, 呉 繁夫, 松原 洋一, 青木 洋子

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2LBA092]-[2LBA092]　2015/12

    Publisher: (公社)日本生化学会

  112. 先天性退形生成星細胞腫と乳頭状汗管嚢胞腺腫からBRAF V600E体細胞モザイク変異を検出した1例(A novel genodermatosis syndrome induced by somatic BRAF V600E mosaicism, comprising congenital anaplastic astrocytoma and linear syringocystadenoma papilliferum)

    渡辺 祐子, 新妻 秀剛, 志藤 光介, 力石 健, 園田 順彦, 青木 洋子, 相場 節也, 笹原 洋二, 呉 繁夫

    日本小児血液・がん学会雑誌　52　(4)　248-248　2015/10

    Publisher: (一社)日本小児血液・がん学会

    ISSN： 2187-011X

    eISSN： 2189-5384

  113. RASopathies and hematologic abnormalities

    Yoko Aoki

    [Rinshō ketsueki] The Japanese journal of clinical hematology　56　(10)　2240-2247　2015/10/01

    Publisher: The Japanese Society of Hematology

    DOI： 10.11406/rinketsu.56.2240 　

    ISSN： 0485-1439

  114. 網羅的ゲノム解析によって候補遺伝子が明らかになった潜因性West症候群

    福與 なおみ, 菊池 敦生, 市野井 那津子, 新堀 哲也, 佐藤 亮, 工藤 宏紀, 佐藤 優子, 中山 東城, 柿坂 庸介, 久保田 由紀, 小林 朋子, 植松 貢, 青木 洋子, 萩野谷 和裕, 呉 繁夫

    てんかん研究　33　(2)　512-512　2015/09

    Publisher: (一社)日本てんかん学会

    ISSN： 0912-0890

    eISSN： 1347-5509

  115. BRAF V600E変異により先天性退形成性星細胞腫を生じたSchimmelpenning症候群の1例

    渡辺 祐子, 新妻 秀剛, 堅田 有宇, 飯塚 千恵, 森谷 邦彦, 南條 由佳, 力石 健, 笹原 洋二, 呉 繁夫, 志藤 光介, 相場 節也, 新堀 哲也, 青木 洋子, 斎藤 竜太, 園田 順彦, 冨永 悌二, 渡辺 みか

    日本小児血液・がん学会雑誌　52　(2)　196-196　2015/08

    Publisher: (一社)日本小児血液・がん学会

    ISSN： 2187-011X

    eISSN： 2189-5384

  116. The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

    Bruce Korf, Reza Ahmadian, Judith Allanson, Yoko Aoki, Annette Bakker, Emma Burkitt Wright, Brian Denger, Ype Elgersma, Bruce D. Gelb, Karen W. Gripp, Bronwyn Kerr, Maria Kontaridis, Conxi Lazaro, Corinne Linardic, Reymundo Lozano, Calum A. MacRae, Ludwine Messiaen, Sonia Mulero-Navarro, Benjamin Neel, Scott Plotkin, Katherine A. Rauen, Amy Roberts, Alcino J. Silva, Sitta G. Sittampalam, Chao Zhang, Lisa Schoyer

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　167　(8)　1741-1746　2015/08

    DOI： 10.1002/ajmg.a.37089 　

    ISSN： 1552-4825

    eISSN： 1552-4833

  117. BRAF V600E変異により先天性退形成性星細胞腫を生じたSchimmelpenning症候群の1例

    堅田 有宇, 渡辺 祐子, 新妻 秀剛, 飯塚 千恵, 高橋 俊成, 内田 崇, 森谷 邦彦, 南條 由佳, 君和田 友美, 渡辺 みか, 新堀 哲也, 青木 洋子, 相場 節也, 力石 健, 笹原 洋二, 園田 順彦, 冨永 悌二, 呉 繁夫

    日本小児科学会雑誌　119　(5)　932-932　2015/05

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  118. 潜因性West症候群に対する網羅的ゲノム解析による遺伝学的診断の有用性

    菊池 敦生, 福與 なおみ, 市野井 那津子, 新堀 哲也, 佐藤 亮, 工藤 宏紀, 佐藤 優子, 中山 東城, 柿坂 庸介, 久保田 由紀, 小林 朋子, 植松 貢, 青木 洋子, 萩野谷 和裕, 呉 繁夫

    脳と発達　47　(Suppl.)　S339-S339　2015/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  119. Application of the Targeted Next Generation Sequencing to the Comprehensive Analysis of Pancreatitis Susceptibility Genes

    Eriko Nakano, Atsushi Masamune, Tetsuya Niihori, Kiyoshi Kume, Shin Hamada, Yoko Aoki, Tooru Shimosegawa

    GASTROENTEROLOGY　148　(4)　S339-S339　2015/04

    ISSN： 0016-5085

    eISSN： 1528-0012

  120. BRAFの免疫染色によってSyringocyst adenoma papilliferumの遺伝子変異箇所を確認し得た1例

    志藤 光介, 渡辺 祐子, 新堀 哲也, 青木 洋子, 呉 繁夫

    日本皮膚科学会雑誌　125　(4)　930-930　2015/04

    Publisher: (公社)日本皮膚科学会

    ISSN： 0021-499X

    eISSN： 1346-8146

  121. Cardio-facio-cutaneous症候群のモデルマウス作製とその病態解析

    青木 洋子, 井上 晋一, 守谷 充司, 大場 大樹, 新堀 哲也, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　119　(2)　276-276　2015/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  122. BRAF V600E変異により先天性退形成性星細胞腫を生じたSchimmelpenning症候群の一例

    堅田 有宇, 渡辺 祐子, 新妻 秀剛, 森谷 邦彦, 南條 由佳, 力石 健, 笹原 洋二, 青木 洋子, 園田 順彦, 呉 繁夫

    日本小児科学会雑誌　119　(2)　293-293　2015/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  123. 潜因性West症候群の網羅的ゲノム解析―18症例中9例で候補変異を同定―

    菊池敦生, 福與なおみ, 福與なおみ, 市野井那津子, 新堀哲也, 佐藤亮, 鈴木資, 工藤宏紀, 佐藤優子, 中山東城, 柿坂庸介, 柿坂庸介, 久保田由紀, 小林朋子, 小林朋子, 舟山亮, 中山啓子, 植松貢, 青木洋子, 萩野谷和裕, 呉繁夫

    日本人類遺伝学会大会プログラム・抄録集　60th　248　2015

  124. COL4A1遺伝子変異が原因と考えられるてんかん性脳症の1例

    福與なおみ, 福與なおみ, 菊池敦生, 佐藤優子, 柿坂庸介, 久保田由紀, 遠藤若葉, 小林朋子, 植松貢, 佐藤亮, 市野井那津子, 萩野谷和裕, 新堀哲也, 新堀哲也, 青木洋子, 青木洋子, 呉繁夫

    日本人類遺伝学会大会プログラム・抄録集　60th　260　2015

  125. Dysferlin遺伝子診断への次世代シークエンサーの導入

    高橋俊明, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 加藤昌昭, 島倉奈緒子, 鈴木直輝, 新堀哲也, 青木洋子, 小野洋也, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    国立病院総合医学会抄録集(CD-ROM)　69th　ROMBUNNO.O-74-5　2015

  126. 小児科・産科領域疾患の大規模遺伝子解析ネットワークとエピゲノム解析拠点整備に関する研究 神経変性疾患・遺伝性筋疾患の遺伝子解析

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 加藤昌昭, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    小児科・産科領域疾患の大規模遺伝子解析ネットワークとエピゲノム解析拠点整備に関する研究 平成26年度 委託業務成果報告書　19-20　2015

  127. Dysferlin遺伝子解析への次世代シークエンサーの導入

    高橋俊明, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 島倉奈緒子, 鈴木直輝, 新堀哲也, 青木洋子, 小野洋也, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　60th　295　2015

  128. 難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 日本人ジスフェルリン異常症の遺伝子変異について

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 加藤昌昭, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 平成26年度 総括・分担研究報告書　17‐18　2015

  129. 当分野におけるヌーナン症候群及び類縁疾患の遺伝子解析の現状

    新堀 哲也, 矢尾板 全子, 守谷 充司, 井泉 瑠美子, 大場 大樹, 西山 亜由美, 井上 晋一, 呉 繁夫, 松原 洋一, 青木 洋子

    日本小児科学会雑誌　118　(5)　876-877　2014/05

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  130. TBX1遺伝子変異が同定された家族性副甲状腺機能低下症の1例 Peer-reviewed

    川島 彰透, 天野 綾, 山田 倫子, 浜松 圭太, 山田 豪, 村部 浩之, 横田 敏彦, 青木 洋子, 新堀 哲也, 緒方 勤

    日本内分泌学会雑誌　90　(1)　295-295　2014/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  131. 眼疾患と遺伝子 緑内障のゲノム解析 次世代医療・個別化医療に向けて

    布施 昇男, 清水 愛, 木村 雅恵, 高野 良真, 石 棟, 宮澤 晃子, 国松 志保, 劉 孟林, 渡邉 亮, 安田 正幸, 横山 悠, 檜森 紀子, 津田 聡, 山本 耕太郎, 中澤 徹, 安田 純, 勝岡 史城, 小島 要, 成相 直樹, 松本 光代, 元池 育子, 長崎 正朗, 木下 賢吾, 五十嵐 和彦, 山本 雅之, 新堀 哲也, 青木 洋子, 松原 洋一, 舟山 亮, 長嶋 剛史, 中山 啓子, 眞島 行彦, 船山 智代, 田中 光一, 原田 高幸, 阿部 春樹, 福地 健郎, 安田 典子, 出田 秀尚, 鄭 暁東, 白石 敦, 大橋 裕一, 石田 誠夫, 原 岳, 金森 章泰, 山田 裕子, 中村 誠, 酒井 寛, Richards Julia E

    日本眼科学会雑誌　118　(3)　216-240　2014/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  132. 過剰マーカー染色体の存在からcat eye syndromeと診断した小眼球症の1例

    守谷 充司, 飯倉 立夏, 矢尾板 全子, 井泉 瑠美子, 菅野 潤子, 新堀 哲也, 青木 洋子, 原田 直樹, 松原 洋一

    日本小児科学会雑誌　118　(3)　572-572　2014/03

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  133. Whole exome and genome sequencing

    62　(2)　111-116　2014/02

    Publisher: 医学の世界社

    ISSN： 0045-7167

  134. 重症Noonan症候群ではCFC症候群の可能性を考慮せよ

    里見 瑠璃, 榎本 啓典, 松村 雄, 寺内 真理子, 嘉川 忠博, 土井 庄三郎, 新堀 哲也, 青木 洋子, 太田 正康

    日本小児科学会雑誌　118　(2)　337-337　2014/02

    ISSN： 0001-6543

  135. ヌーナン症候群の新規原因遺伝子RIT1の同定

    青木 洋子, 新堀 哲也, 岡本 伸彦, 水野 誠司, 黒澤 健司, 緒方 勤, 井上 晋一, 松原 洋一

    日本小児科学会雑誌　118　(2)　209-209　2014/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  136. 【膵基礎研究:膵疾患の病因・病態解明に挑む】 膵炎の原因遺伝子探索

    正宗 淳, 中野 絵里子, 粂 潔, 新堀 哲也, 青木 洋子, 下瀬川 徹

    膵臓　29　(1)　51-58　2014

    DOI： 10.2958/suizo.29.51 　

  137. 【肝胆膵診療のNew Horizon】 膵疾患 慢性膵炎 膵炎の原因遺伝子はどこまで解ったか

    正宗 淳, 中野 絵里子, 粂 潔, 新堀 哲也, 青木 洋子, 下瀬川 徹

    肝・胆・膵　69　(6)　1115-1121　2014

  138. 筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 次世代シークエンサーを用いた遠位型ミオパチーにおけるゲノム解析

    青木正志, 井泉瑠美子, 高橋俊明, 加藤昌昭, 鈴木直輝, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 平成23-25年度 総括研究報告書　15-16　2014

  139. 次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 次世代シークエンサーを用いた遺伝性筋疾患におけるゲノム解析

    青木正志, 井泉瑠美子, 加藤昌昭, 割田仁, 鈴木直輝, 竪山真規, 高橋俊明, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子, 松原洋一

    次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 平成25年度 総括・分担研究報告書　11-13　2014

  140. 次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 次世代シークエンサーを用いた遺伝性筋疾患におけるゲノム解析

    青木正志, 井泉瑠美子, 加藤昌昭, 割田仁, 鈴木直輝, 竪山真規, 高橋俊明, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子, 松原洋一

    次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 平成23-25年度 総合研究報告書　11-14　2014

  141. Myofibrillar myopathyの大家系での次世代シークエンサーを用いた原因遺伝子の同定

    井泉 瑠美子, 新堀 哲也, 青木 洋子, 鈴木 直輝, 加藤 昌昭, 割田 仁, 高橋 俊明, 竪山 真規, 長嶋 剛史, 舟山 亮, 中山 啓子, 松原 洋一, 青木 正志

    臨床神経学　53　(12)　1450-1450　2013/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  142. Application of next-generation sequencing to searching for disease-causing genes and genetic testing

    245　(5)　358-362　2013/05/04

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  143. 次世代シークエンサーを用いたヌーナン症候群の遺伝子診断と新規原因遺伝子検索

    青木洋子, 新堀哲也, 井上晋一, 松原洋一

    日本小児科学会雑誌　117　(2)　314　2013/02/01

    ISSN： 0001-6543

  144. 次世代シークエンサーを用いた新規発達緑内障遺伝子の探索

    清水愛, 新堀哲也, 青木洋子, 松原洋一, 舟山亮, 長嶋剛史, 中山啓子, 渡邉亮, 長崎正朗, 布施昇男, 中澤徹

    日本眼科学会雑誌　117　2013

    ISSN： 0029-0203

  145. エクソームシークエンスによるNoonan症候群新規原因遺伝子RIT1の同定

    新堀哲也, 青木洋子, 番匠俊博, 岡本伸彦, 水野誠司, 黒澤健司, 緒方勤, 高田史男, 長谷川奉延, 舟山亮, 長嶋剛史, 中山啓子, 井上晋一, 渡邊裕介, 小椋利彦, 松原洋一

    日本人類遺伝学会大会プログラム・抄録集　58th　119　2013

  146. Myofibrillar myopathyの大家系での次世代シークエンサーを用いた原因遺伝子の同定

    井泉瑠美子, 井泉瑠美子, 新堀哲也, 青木洋子, 鈴木直輝, 加藤昌昭, 割田仁, 高橋俊明, 竪山真規, 長嶋剛史, 舟山亮, 中山啓子, 松原洋一, 青木正志

    日本神経学会学術大会プログラム・抄録集　54th　332　2013

  147. Myofibrillar myopathyの大家系における次世代型シークエンサーを用いた新たな原因遺伝子の同定

    井泉瑠美子, 新堀哲也, 青木洋子, 鈴木直輝, 加藤昌昭, 割田仁, 高橋俊明, 竪山真規, 長嶋剛史, 舟山亮, 阿部康二, 中山啓子, 青木正志, 松原洋一

    日本人類遺伝学会大会プログラム・抄録集　58th　136　2013

  148. Turner症候群、Noonan症候群

    青木洋子, 松原洋一

    周産期医学　43　359-362　2013

  149. MAP キナーゼと先天異常

    青木洋子

    Clinical Neuroscience　43　695-698　2013

  150. 次世代シークエンサーを用いた遺伝学的検査

    青木洋子, 新堀哲也, 松原洋一

    小児科診療　76　1099-1104　2013

  151. Costello症候群

    青木洋子

    小児内科　45　1051-1952　2013

  152. Noonan・CFC・Costello症候群（RASopathies or RAS/MAPK pathway syndromes)

    青木洋子, 松原洋一

    小児科臨床増刊号　66　1375-1381　2013

  153. 広範囲の欠失とミスセンスの複合ヘテロ接合体遺伝子変異を持つ異染性白質ジストロフィーの出生前遺伝子診断

    開山麻美, SEO Joo Hyun, 小須賀基通, 木田和宏, 秦健一郎, 右田王介, 青木洋子, 松原洋一, 奥山虎之

    日本先天代謝異常学会雑誌　28　179-179　2012/10/12

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  154. コステロ症候群・CFC症候群の全国実態調査とその病態の解明に関する研究

    阿部 裕, 青木 洋子, 栗山 進一, 川目 裕, 岡本 伸彦, 黒澤 健司, 大橋 博文, 水野 誠司, 緒方 勤, 呉 繁夫, 新堀 哲也, 松原 洋一

    日本小児科学会雑誌　116　(5)　888-888　2012/05

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  155. Noonan症候群類縁疾患と小児血液腫瘍におけるCBLの分子遺伝学的解析

    齋藤 由佳, 青木 洋子, 村松 秀樹, 今泉 益栄, 力石 健, 笹原 洋二, 呉 繁夫, 新堀 哲也, 小島 勢二, 松原 洋一

    日本小児科学会雑誌　116　(2)　246-246　2012/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  156. コステロ症候群・CFC症候群の全国実態調査とその病態の解明に関する研究

    阿部 裕, 青木 洋子, 新堀 哲也, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　116　(2)　294-294　2012/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  157. 全ゲノム関連解析による最初のもやもや病遺伝子 RNF213の同定

    鎌田 文顕, 青木 洋子, 成澤 あゆみ, 阿部 裕, 小松崎 匠子, 菅野 潤子, 新堀 哲也, 松原 洋一, 呉 繁夫, 菊池 敦生, 土屋 滋, 藤村 幹, 冨永 悌二, 小野 栄夫, 石井 直人, 大和田 祐二, 真下 陽一, 鈴木 洋一, 羽田 明

    日本小児科学会雑誌　115　(9)　1478-1478　2011/09

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  158. コステロ症候群・CFC症候群の全国実態調査とその病態に関する研究

    松原 洋一, 阿部 裕, 新堀 哲也, 黒澤 健司, 岡本 伸彦, 水野 誠司, 大橋 博文, 川目 裕, 緒方 勤, 呉 繁夫, 栗山 進一, 青木 洋子

    日本遺伝カウンセリング学会誌　32　(2)　76-76　2011/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  159. コステロ症候群・CFC症候群の全国実態調査とその病態に関する研究

    松原 洋一, 阿部 裕, 新堀 哲也, 黒澤 健司, 岡本 伸彦, 水野 誠司, 大橋 博文, 川目 裕, 緒方 勤, 呉 繁夫, 栗山 進一, 青木 洋子

    家族性腫瘍　11　(2)　A76-A76　2011/05

    Publisher: 日本家族性腫瘍学会

    ISSN： 1346-1052

    eISSN： 2189-6674

  160. Cardio-Facio-Cutaneous Syndrome: Does Genotype Predict Phenotype?

    Judith E. Allanson, Goran Anneren, Yoki Aoki, Christine M. Armour, Marie-Louise Bondeson, Helene Cave, Karen W. Gripp, Bronwyn Kerr, Anna-Maja Nystrom, Katia Sol-Church, Alain Verloes, Martin Zenker

    AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS　157C　(2)　129-135　2011/05

    DOI： 10.1002/ajmg.c.30295 　

    ISSN： 1552-4868

  161. Clinical, Pathological, and Molecular Analyses of Cardiovascular Abnormalities in Costello Syndrome: A Ras/MAPK Pathway Syndrome

    Angela E. Lin, Mark E. Alexander, Steven D. Colan, Bronwyn Kerr, Katherine A. Rauen, Jacqueline Noonan, Jeanne Baffa, Elizabeth Hopkins, Katia Sol-Church, Giuseppe Limongelli, Maria Christina Digilio, Bruno Marino, A. Micheil Innes, Yoko Aoki, Michael Silberbach, Marie-Ange Delrue, Susan M. White, Robert M. Hamilton, William O&apos;Connor, Paul D. Grossfeld, Leslie B. Smoot, Robert F. Padera, Karen W. Gripp

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　155A　(3)　486-507　2011/03

    DOI： 10.1002/ajmg.a.33857 　

    ISSN： 1552-4825

  162. モヤモヤ病遺伝的要因の解明 疾患感受性遺伝子と創始者変異の同定

    呉 繁夫, 鎌田 文顕, 青木 洋子, 阿部 裕, 新堀 哲也, 小松崎 匠子, 菊池 敦生, 菅野 潤子, 土屋 滋, 松原 洋一

    日本小児科学会雑誌　115　(2)　294-294　2011/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  163. RASシグナル伝達異常症の分子メカニズム

    青木洋子, 斎藤由佳, 松原洋一

    (25)　1-7　2011

  164. ピリドキシン依存性けいれん患者の臨床像とALDH変異解析による遺伝学的背景の検討

    菅野 潤子, 呉 繁夫, 坂本 修, 青木 洋子, 松原 洋一, 土屋 滋

    日本先天代謝異常学会雑誌　26　(2)　128-128　2010/09

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  165. Molecular genetics of congenital anomaly syndromes (RAS/MAPK syndromes) complicated with malignancies. (Rinsho Ketsueki)

    Aoki Yoko, Matsubara Yoichi

    Rinsho Ketsueki　51　(7)　532-538　2010/07

    DOI： 10.11406/rinketsu.51.532 　

  166. Noonan症候群類縁疾患 (ホルモンと臨床)

    青木洋子

    ホルモンと臨床　58　(7)　77-82　2010/07/01

  167. Noonan症候群類縁疾患におけるRAF1遺伝子解析とその発症メカニズムの解析

    小林 朋子, 青木 洋子, 新堀 哲也, 鳴海 洋子, 小松崎 匠子, 土屋 滋, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　114　(2)　190-190　2010/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  168. ピリドキシン依存性けいれん患者の臨床像とALDH変異解析による遺伝学的背景の検討

    菅野 潤子, 坂本 修, 青木 洋子, 呉 繁夫, 松原 洋一, 土屋 滋

    日本小児科学会雑誌　114　(2)　194-194　2010/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  169. 【最近話題の遺伝子異常による内分泌および類縁疾患】 Noonan症候群類縁疾患 (ホルモンと臨床)

    青木洋子, 松原洋一

    ホルモンと臨床　58　(7)　619-623　2010

  170. Costello症候群・CFC症候群―RASがん原遺伝子の生殖細胞変異― (小児内科)

    青木洋子, 新堀哲也, 松原洋一

    小児内科　41　(11)　1657-1662　2009/11

  171. Costello症候群 (小児疾患診療のための病態生理、小児内科)

    青木洋子

    小児疾患診療のための病態生理、小児内科　41　325-329　2009/08

  172. Noonan症候群 (小児疾患診療のための病態生理、小児内科)

    Noonan症候群

    小児疾患診療のための病態生理、小児内科　41　273-277　2009/08

  173. Costello症候群, cardio-facio-cutaneous症候群 (小児科)

    青木洋子, 松原洋一

    小児科　50　(7)　872-875　2009/06

  174. RAS/MAPK経路異常症の臨床遺伝学 (小児科診療)

    青木洋子

    小児科診療　72　(1)　117-122　2009/01

  175. 当科で経験したファブリー病の2家系の遺伝カウンセリング

    小松崎 匠子, 小林 朋子, 新堀 哲也, 青木 洋子, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　112　(9)　1428-1428　2008/09

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  176. デュシェンヌ型筋ジストロフィ家系の女性において保因者診断を行った1例

    新堀 哲也, 小林 朋子, 小松崎 匠子, 青木 洋子, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　112　(9)　1428-1429　2008/09

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  177. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. International-journal

    Yoko Aoki, Tetsuya Niihori, Yoko Narumi, Shigeo Kure, Yoichi Matsubara

    Human mutation　29　(8)　992-1006　2008/08

    DOI： 10.1002/humu.20748 　

    More details Close

    The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).

  178. 隙間のある中切歯・眼間開離・体幹の筋緊張低下・手指の屈曲拘縮から疑われBCB染色により確定診断に至ったX連鎖αサラセミア・精神遅滞症候群(ATRX)の1例

    小松崎 匠子, 青木 洋子, 呉 繁夫, 松原 洋一, 萩野谷 和裕, 大野 忠行, 松田 直, 和田 敬仁

    日本小児科学会雑誌　112　(3)　533-533　2008/03

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  179. Noonan症候群類縁疾患におけるSOS1遺伝子解析と臨床像の検討

    鳴海 洋子, 青木 洋子, 新堀 哲也, 小林 朋子, 西尾 公男, 大橋 博文, 黒澤 健司, 川目 裕, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　112　(2)　226-226　2008/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  180. グリシン脳症の発症機序 グリシン開裂酵素系の部分及び完全欠損マウスを用いた解析

    呉 繁夫, 小松崎 匠子, 菅野 潤子, 鎌田 文顕, 青木 洋子, 松原 洋一

    日本小児科学会雑誌　112　(2)　251-251　2008/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  181. Molecular aspects, clinical aspects and possible treatment modalities for Costello syndrome: proceedings from the 1st International Costello Syndrome Research Symposium 2007.

    Rauen Katherine A, Hefner Erin, Carrillo Kristin, Taylor Jill, Messier Laure, Aoki Yoko, Gripp Karen W, Matsubara Yoichi, Proud Virginia K, Hammond Peter, Allanson Judith E, Delrue Marie-Ange, Axelrad Marni E, Lin Angela E, Doyle Daniel A, Kerr Bronwyn, Carey John C, McCormick Frank, Silva Alcino J, Kieran Mark W, Hinek Aleksander, Nguyen Tan T, Schoyer Lisa

    Am J Med Genet A　146　(9)　1205-1217　2008

    DOI： 10.1002/ajmg.a.32276 　

  182. Multiplex ligation-dependent probe amplification(MLPA)法 非ケトーシス型高グリシン血症の遺伝子診断への応用 (日本マス・スクリーニング学会誌)

    菅野潤子, 呉繁夫, 青木洋子, 松原洋一

    日本マス・スクリーニング学会誌　17　(3)　9-17　2007/12

  183. ピリドキシン依存性けいれん ALDH7A1変異解析で見出された遺伝的背景の異質性

    菅野 潤子, 呉 繁夫, 成澤 あゆみ, 鎌田 文顕, 青木 洋子, 土屋 滋, 松原 洋一

    日本先天代謝異常学会雑誌　23　(1)　134-134　2007/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  184. DNAメチル化テスト、15q11-q13多型解析および刷り込み中心領域の定量PCRにて、欠失の診断を得られたPrader-Willi症候群の1男児例

    菅野 潤子, 青木 洋子, 呉 繁夫, 松原 洋一, 坂本 修, 萩野谷 和裕, 土屋 滋, 斎藤 伸治

    日本小児科学会雑誌　111　(9)　1215-1215　2007/09

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  185. 遺伝子診断の新しい流れ Noonan症候群、Costello症候群、cardio-facio-cutaneous症候群の包括的遺伝子診断

    青木 洋子, 新堀 哲也, 鳴海 洋子, 川目 裕, 黒澤 健司, 大橋 博文, 岡本 伸彦, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　111　(2)　141-141　2007/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  186. 遺伝子診断の新しい流れ 小児科外来・ベッドサイドで実施可能な迅速・簡便な遺伝子診断法の開発と応用

    呉 繁夫, 鎌田 文顕, 菅野 潤子, 鳴海 洋子, 新堀 哲也, 青木 洋子, 松原 洋一

    日本小児科学会雑誌　111　(2)　142-142　2007/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  187. ピリドキシン依存性けいれん ALDH7A1変異解析で見出された遺伝的背景の異質性

    菅野 潤子, 呉 繁夫, 鎌田 文顕, 山本 克哉, 後藤 知英, 高橋 孝雄, 萩野谷 和裕, 土屋 滋, 青木 洋子, 松原 洋一

    日本小児科学会雑誌　111　(2)　187-187　2007/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  188. Cardio-facio-cutaneous症候群の遺伝子解析と臨床像の検討

    鳴海 洋子, 青木 洋子, 新堀 哲也, 岡本 伸彦, 黒澤 健司, 大橋 博文, 蒔田 芳男, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　111　(2)　188-188　2007/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  189. Human development and the RAS/MAPK pathway

    Yoko Aoki, Yoichi Matsubara

    SEIKAGAKU　79　(1)　34-38　2007/01

    ISSN： 0037-1017

  190. Wild-type PAH activity is enhanced by BH4 supplementation in vivo: Implication for mechanism of BH4 responsiveness

    S. Kure, K. Sato, K. Fujii, Y. Aoki, Y. Suzuki, Y. Matsubara

    JOURNAL OF INHERITED METABOLIC DISEASE　29　14-14　2006/08

    ISSN： 0141-8955

  191. Rapid diagnosis of glycine encephalopathy by C-13-glycine breath test

    S. Kure, S. H. Korman, J. Kanno, M. Kubota, M. Takayanagi, A. Matsui, Y. Aoki, T. Ohura, Y. Matsubara

    JOURNAL OF INHERITED METABOLIC DISEASE　29　110-110　2006/08

    ISSN： 0141-8955

  192. Dysregulation of the RAS/MAPK pathway causes Costello syndrome and cardio-facio-cutaneous (CFC) syndrome

    Y. Aoki, T. Niihori, Y. Narumi, H. Kawame, K. Kurosawa, H. Ohashi, M. Filocamo, Y. Suzuki, S. Kure, Y. Matsubara

    JOURNAL OF INHERITED METABOLIC DISEASE　29　50-50　2006/08

    ISSN： 0141-8955

  193. Genomic deletion within GLDC is a major cause of nonketotic hyperglycinemia: Screening of 65 patients by multiplex ligation-dependent probe amplification

    J. Kanno, T. Hutchin, F. Kamada, A. Narisawa, Y. Aoki, Y. Matsubara, S. Kure

    JOURNAL OF INHERITED METABOLIC DISEASE　29　109-109　2006/08

    ISSN： 0141-8955

  194. 小児科学・医療にブレークスルーをもたらした症例・研究 フェニルケトン尿症に対する経口治療薬の同定とその臨床的意義

    呉 繁夫, 大浦 敏博, 岩本 弘子, 鈴木 周平, 杉山 成司, 坂本 修, 藤井 邦裕, 青木 洋子, 成澤 邦明, 松原 洋一

    日本小児科学会雑誌　110　(2)　145-145　2006/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  195. 新しい欠失変異検出法であるMLPA法による非ケトーシス型高グリシン血症の遺伝子診断

    菅野 潤子, 呉 繁夫, 青木 洋子, 松原 洋一

    日本小児科学会雑誌　110　(2)　188-188　2006/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  196. 小児科学・医療にブレークスルーをもたらした症例・研究 HRAS原癌遺伝子の生殖細胞変異はコステロ症候群を引き起こす

    青木 洋子, 新堀 哲也, 川目 裕, 黒澤 健司, 大橋 博文, 田中 祐吉, 鳴海 洋子, 鈴木 洋一, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　110　(2)　146-146　2006/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  197. 【シグナル伝達病を知る その分子機序解明から新たな治療戦略まで】 臨床応用編 循環器疾患とシグナル RAS/MAPKシグナル伝達とヒト先天異常症 (遺伝子医学MOOK)

    青木洋子, 松原洋一

    遺伝子医学MOOK　(6)　306-312　2006

  198. Multiplex ligation-dependent probe amplification法による非ケトーシス型高グリシン血症の遺伝子診断

    菅野 潤子, 呉 繁夫, 青木 洋子, 松原 洋一, Hutchin Tim

    日本先天代謝異常学会雑誌　21　(2)　62-62　2005/11

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  199. アミノグリコシド系抗生剤による難聴:ミトコンドリア1555A>G変異の遺伝子検査と遺伝相談

    呉 繁夫, 菅野 潤子, 青木 洋子, 松原 洋一, 平塚 真弘

    日本小児科学会雑誌　109　(10)　1266-1267　2005/10

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  200. Mutations in the holocarboxylase synthetase gene HLCS

    Y Suzuki, Yang, X, Y Aoki, S Kure, Y Matsubara

    HUMAN MUTATION　26　(4)　285-290　2005/10

    DOI： 10.1002/humu.20204 　

    ISSN： 1059-7794

  201. GSTP1遺伝子多型と気管支喘息との相関

    鎌田 文顕, 新堀 哲也, 邵 晨ちん, 青木 洋子, 呉 繁夫, 松原 洋一, 鈴木 洋一, 玉利 真由美, 長谷川 耕一, 広田 朝光, 清水 麻貴子, 高橋 尚美, 土居 悟, 藤原 寛, 宮武 昭彦, 藤田 きみゑ, 榎本 雅夫, 川合 満, 佐々木 聖, 森川 利夫, 森川 みき, 千葉 靖, 田村 弦, 白川 太郎

    アレルギー　54　(8-9)　1058-1058　2005/09

    Publisher: (一社)日本アレルギー学会

    ISSN： 0021-4884

  202. Involvement and Function of Mutant Tyrosine Phosphatase, Shp-2, in Childhood Leukemia

    IMAIZUMI Masue, AOKI Yoko

    19　(3)　152-157　2005/06/30

    ISSN： 0913-8706

  203. ヌーナン症候群と小児白血病の遺伝子解析と変異蛋白の生化学的解析

    新堀 哲也, 青木 洋子, 鈴木 洋一, 呉 繁夫, 松原 洋一, 藤井 邦裕

    日本小児科学会雑誌　109　(3)　415-416　2005/03

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  204. 日本人ビタミンB12反応性メチルマロン酸血症の遺伝子解析

    坂本 修, 楊 雪, 松原 洋一, 鈴木 洋一, 呉 繁夫, 青木 洋子, 飯沼 一宇, 大浦 敏博

    日本小児科学会雑誌　109　(2)　152-152　2005/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  205. ヌーナン症候群と小児白血病の遺伝子解析と変異蛋白の生化学的解析

    青木 洋子, 新堀 哲也, 黒澤 健司, 大橋 博文, 近藤 達郎, 鈴木 洋一, 呉 繁夫, 今泉 益栄, 松原 洋一

    日本小児科学会雑誌　109　(2)　157-157　2005/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  206. 補体系C3,C3AR1,C5遺伝子の多型は喘息発症リスクに影響する

    鎌田 文顕, 鈴木 洋一, 青木 洋子, 呉 繁夫, 松原 洋一, 長谷川 耕一, 玉利 真由美, 白川 太郎

    日本小児アレルギー学会誌　18　(4)　477-477　2004/10

    Publisher: 日本小児アレルギー学会

    ISSN： 0914-2649

  207. 正常マウスのBH4反応性からみたBH4反応性フェニルアラニン水酸化酵素欠損症の発症機序

    呉 繁夫, 佐藤 健一, 藤井 邦裕, 青木 洋子, 鈴木 洋一, 加藤 晴一, 松原 洋一

    日本先天代謝異常学会雑誌　20　(2)　138-138　2004/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  208. ヌーナン症候群と小児白血病の遺伝子解析と変異蛋白の生化学的解析

    青木 洋子, 新堀 哲也, 大橋 博文, 黒澤 健司, 近藤 達郎, 呉 繁夫, 鈴木 洋一, 今泉 益栄, 松原 洋一

    日本先天代謝異常学会雑誌　20　(2)　169-169　2004/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  209. 日本人ビタミンB12反応性メチルマロン酸血症の遺伝子解析

    坂本 修, 楊 雪, 松原 洋一, 鈴木 洋一, 呉 繁夫, 青木 洋子, 飯沼 一宇, 大浦 敏博

    日本先天代謝異常学会雑誌　20　(2)　211-211　2004/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  210. 補体系C3,C3AR1,C5遺伝子の多型は喘息発症リスクに影響する

    鎌田 文顕, 鈴木 洋一, 青木 洋子, 呉 繁夫, 松原 洋一, 長谷川 耕一, 玉利 真由美, 白川 太郎

    アレルギー　53　(8-9)　901-901　2004/09

    Publisher: (一社)日本アレルギー学会

    DOI： 10.15036/arerugi.53.901_4 　

    ISSN： 0021-4884

  211. テトラヒドロビオプテリン(BH4)反応性フェニルアラニン水酸化酵素欠損症におけるBH4反応性の機序

    呉 繁夫, 佐藤 健一, 藤井 邦裕, 青木 洋子, 鈴木 洋一, 加藤 晴一, 松原 洋一

    日本マス・スクリーニング学会誌　14　(2)　54-54　2004/09

    Publisher: 日本マススクリーニング学会

    ISSN： 0917-3803

  212. 技術解説 先天性代謝・内分泌疾患の遺伝子異常についての最新の知見 糖原病I型の遺伝子診断

    松原 洋一, 呉 繁夫, 小島 加奈子, 鎌田 文顕, 藤井 邦裕, 鈴木 洋一, 青木 洋子

    日本マス・スクリーニング学会誌　14　(1)　67-74　2004/06

    Publisher: 日本マススクリーニング学会

    ISSN： 0917-3803

  213. ヌーナン症候群とJMMLの遺伝子解析と変異蛋白の生化学的解析

    青木 洋子, 新堀 哲也, 黒澤 健司, 大橋 博文, 近藤 達郎, 今泉 益栄, 鈴木 洋一, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　108　(2)　149-149　2004/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  214. ベッドサイド遺伝子診断のための簡便な遺伝子多型・変異検出法の開発

    松原 洋一, 呉 繁夫, 鈴木 洋一, 青木 洋子

    日本小児科学会雑誌　108　(2)　149-149　2004/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  215. 日本人プロピオン酸血症の遺伝子変異解析

    坂本 修, 楊 雪, 大浦 敏博, 呉 繁夫, 鈴木 洋一, 青木 洋子, 松原 洋一, 飯沼 一宇

    日本小児科学会雑誌　108　(2)　151-151　2004/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  216. 補体系C3,C3AR1,C5遺伝子の多型は喘息発症リスクに影響する

    鈴木 洋一, 鎌田 文顕, Shao Chenchen, 青木 洋子, 呉 繁夫, 長谷川 耕一, 玉利 真由美, 白川 太郎, 松原 洋一

    日本小児科学会雑誌　108　(2)　160-160　2004/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  217. 「ADHDを伴う軽度精神遅滞」と診断された症例を含む軽症型高グリシン血症3症例

    呉 繁夫, 一戸 明子, 小島 加奈子, 青木 洋子, 鈴木 洋一, 松原 洋一

    日本小児科学会雑誌　108　(2)　187-187　2004/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  218. Linkage and association of childhood asthma with the chromosome 12 genes

    Chenchen Shao, Yoichi Suzuki, Fumiaki Kamada, Kiyoshi Kanno, Mayumi Tamari, Koichi Hasegawa, Yoko Aoki, Shigeo Kure, Xue Yang, Hiroko Endo, Reiko Takayanagi, Chifuyu Nakazawa, Toshio Morikawa, Miki Morikawa, Shigeaki Miyabayashi, Yasushi Chiba, Minoru Karahashi, Seichi Saito, Gen Tamura, Taro Shirakawa, Yoichi Matsubara

    Journal of Human Genetics　49　(3)　115-122　2004

    DOI： 10.1007/s10038-003-0118-z 　

    ISSN： 1434-5161

  219. 遺伝性疾患における保因者診断とその遺伝カウンセリング

    新堀 哲也, 鎌田 文顕, 一戸 明子, 小島 加奈子, 呉 繁夫, 鈴木 洋一, 青木 洋子, 松原 洋一

    日本小児科学会雑誌　108　(1)　103-103　2004/01

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  220. Association of the hCLCA1 gene with bronchial asthma

    F Kamada, Y Suzuki, C Shao, M Tamari, K Hasegawa, Y Aoki, S Kure, G Tamura, T Shirakawa, Y Matsubara

    AMERICAN JOURNAL OF HUMAN GENETICS　73　(5)　374-374　2003/11

    ISSN： 0002-9297

  221. 日本人プロピオン酸血症の遺伝子解析

    坂本 修, 楊 雪, 大浦 敏博, 呉 繁夫, 鈴木 洋一, 青木 洋子, 山口 清次, 松原 洋一, 飯沼 一宇

    日本先天代謝異常学会雑誌　19　(2)　170-170　2003/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  222. ベッドサイドや外来診療における迅速遺伝子診断のための新しい点変異検出法(CASSOH法)の開発

    松原 洋一, 呉 繁夫, 鈴木 洋一, 青木 洋子

    日本先天代謝異常学会雑誌　19　(2)　210-210　2003/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  223. グリシン脳症モデルマウスの作成と解析 脳形成異常と痙攣重積

    一戸 明子, 呉 繁夫, 小島 加奈子, 青木 洋子, 鈴木 洋一, 佐藤 康二, 飯沼 一宇, 松原 洋一

    日本先天代謝異常学会雑誌　19　(2)　224-224　2003/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  224. hCLCA1遺伝子多型と気管支喘息との相関

    鎌田 文顕, 鈴木 洋一, 邵 晨ちん, 青木 洋子, 呉 繁夫, 玉利 真由美, 長谷川 耕一, 遠藤 廣子, 高柳 玲子, 中澤 千冬, 森川 利夫, 森川 みき, 宮林 重明, 千葉 靖, 斎藤 誠一, 田村 弦, 白川 太郎, 松原 洋一

    アレルギー　52　(8-9)　846-846　2003/09

    Publisher: (一社)日本アレルギー学会

    DOI： 10.15036/arerugi.52.846_3 　

    ISSN： 0021-4884

  225. hCLCA1遺伝子多型と気管支喘息との相関

    鎌田 文顕, 鈴木 洋一, 邵 晨ちん, 青木 洋子, 呉 繁夫, 玉利 真由美, 長谷川 耕一, 遠藤 廣子, 森川 利夫, 森川 みき, 宮林 重明, 千葉 靖, 斎藤 誠一, 田村 弦, 白川 太郎, 松原 洋一

    日本小児アレルギー学会誌　17　(4)　489-489　2003/09

    Publisher: 日本小児アレルギー学会

    ISSN： 0914-2649

  226. Concerns regarding transience and heterozygosity in neonatal hyperglycenemia [1] (multiple letters)

    Ada Hamosh, Johan Van Hove, Shigeo Kure, Kanako Kojima, Akiko Ichinohe, Tomoki Maeda, Rozalia Kalmanchey, György Fekete, Suzan Z. Berg, Jim Filiano, Yoko Aoki, Yoichi Suzuki, Tatsuro Izumi, Yoichi Matsubara

    Annals of Neurology　53　(5)　685-686　2003/05/01

    ISSN： 0364-5134

  227. 日本人ヌーナン症候群の遺伝子解析

    新堀 哲也, 青木 洋子, 黒澤 健司, 大橋 博文, 近藤 達郎, 楊 雪, 鈴木 洋一, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　107　(2)　236-236　2003/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  228. 高グリシン血症モデルマウスの作成と解析 行動実験とマイクロアレイ遺伝子発現解析

    小島 加奈子, 呉 繁夫, 一戸 明子, 新家 利一, 横山 浩之, 廣瀬 三恵子, 飯沼 一宇, 青木 洋子, 鈴木 洋一, 松原 洋一

    日本小児科学会雑誌　107　(2)　238-238　2003/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  229. hCLCA1遺伝子多型と小児気管支喘息との相関

    鎌田 文顕, 鈴木 洋一, 青木 洋子, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　107　(2)　404-404　2003/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  230. Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion.

    Kayano Shuji, Kure Shigeo, Suzuki Yoichi, Kanno Kiyoshi, Aoki Yoko, Kondo Shinji, Schutte Brian C, Murray Jeffrey C, Yamada Atsushi, Matsubara Yoichi

    J Hum Genet　48　(12)　622-628　2003

    Publisher: Springer-Verlag Tokyo

    DOI： 10.1007/s10038-003-0089-0 　

    ISSN： 1434-5161

  231. Estimation of genetic risk for bronchial asthma by multiple SNPs in candidate genes.

    Y Suzuki, C Shao, F Kamada, M Tamari, K Hasegawa, Yang, X, Y Aoki, S Kure, K Kanno, XQ Mao, JM Hopkin, T Shirakawa, Y Matsubara

    AMERICAN JOURNAL OF HUMAN GENETICS　71　(4)　373-373　2002/10

    ISSN： 0002-9297

  232. Molecular analysis of PTPN11 gene encoding, protein tyrosine phosphatase SHP-2 and phenotype-genotype correlation in Japanese patients with Noonan syndrome.

    Y Aoki, T Niihori, Yang, X, K Kurosawa, H Ohashi, T Kondo, E Ishii, Y Suzuki, S Kure, Y Matsubara

    AMERICAN JOURNAL OF HUMAN GENETICS　71　(4)　527-527　2002/10

    ISSN： 0002-9297

  233. 非ケトーシス高グリシン血症の各病型の遺伝学的背景

    呉 繁夫, 一戸 明子, 小島 加奈子, 青木 洋子, 鈴木 洋一, 松原 洋一

    日本先天代謝異常学会雑誌　18　(2)　116-116　2002/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  234. 非ケトーシス型高グリシン血症における脳形成異常の発症機序解析 グリシン開裂酵素系の神経幹細胞における発現

    一戸 明子, 呉 繁夫, 小島 加奈子, 青木 洋子, 鈴木 洋一, 佐藤 康二, 松原 洋一

    日本先天代謝異常学会雑誌　18　(2)　117-117　2002/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  235. GFAP遺伝子変異が同定されたアレキサンダー病の一例

    青木 洋子, 萩野谷 和裕, 宗形 光敏, 横山 浩之, 西尾 利之, 冨樫 紀子, 伊藤 辰夫, 呉 繁夫, 飯沼 一宇, 松原 洋一

    日本小児科学会雑誌　106　(2)　170-170　2002/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  236. 唇裂・口蓋裂患者におけるGAD67遺伝子の関与の検討

    菅野 貴世史, 鈴木 洋一, 山田 敦, 青木 洋子, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　106　(2)　179-179　2002/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  237. 小児喘息の遺伝的背景の多変量解析による検討

    鈴木 洋一, 邵 晨ちん, 菅野 貴世史, 青木 洋子, 楊 雪, 呉 繁夫, 松原 洋一

    日本小児科学会雑誌　106　(2)　177-177　2002/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  238. 小児期発症の喘息・アトピー性皮膚炎の12番染色体との連鎖

    邵 晨ちん, 鈴木 洋一, 菅野 貴世史, 青木 洋子, 楊 雪, 呉 繁夫, 松原 洋一, 田村 弦, 遠藤 廣子, 高柳 玲子

    アレルギー　50　(9-10)　1006-1006　2001/10

    Publisher: (一社)日本アレルギー学会

    DOI： 10.15036/arerugi.50.1006_2 　

    ISSN： 0021-4884

  239. ドミナント・ネガティブ変異グリシン脱炭酸酵素の過剰発現による高グリシン血症モデルマウスの作成と解析

    小島 加奈子, 呉 繁夫, 新家 利一, 横山 浩之, 広瀬 三恵子, 青木 洋子, 鈴木 洋一, 松原 洋一

    日本先天代謝異常学会雑誌　17　(2)　120-120　2001/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  240. 小児期発症の喘息・アトピー性皮膚炎の12番染色体における連鎖解析

    鈴木 洋一, 邵 晨ちん, 菅野 貴世史, 青木 洋子, 楊 雪, 呉 繁夫, 田村 弦, 遠藤 廣子, 高柳 玲子, 中澤 千冬

    日本小児アレルギー学会誌　15　(4)　468-468　2001/09

    Publisher: 日本小児アレルギー学会

    ISSN： 0914-2649

  241. ホロカルボキシラーゼ合成酵素欠損症におけるビオチン反応性の機序

    坂本 修, 鈴木 洋一, 李 雪, 青木 洋子, 平塚 昌弘, 成澤 邦明

    日本先天代謝異常学会雑誌　17　(1)　34-37　2001/07/01

    ISSN： 0912-0122

  242. 日本人唇裂・口蓋裂患者におけるレチノイン酸受容体α遺伝子の関与の検討

    菅野 貴世史, 鈴木 洋一, 楊 雪梅, 青木 洋子, 呉 繁夫, 成澤 邦明, 山田 敦, 松原 洋一

    日本小児科学会雑誌　105　(3)　324-324　2001/03

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  243. 小児の喘息とアトピー性皮膚炎の遺伝的背景

    鈴木 洋一, 青木 洋子, 楊 雪, 菅野 貴世史, 呉 繁夫, 成澤 邦明, 松原 洋一

    日本小児科学会雑誌　105　(3)　248-248　2001/03

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  244. Mutation spectrum and haplotype analysis of holocarboxylase synthetase gene.

    Y Suzuki, Li, X, Yang, X, O Sakamoto, Y Aoki, M Hiratsuka, K Inui, M Gibson, T Suormala, R Baumgartner, S Kure, Y Matsubara, K Narisawa

    AMERICAN JOURNAL OF HUMAN GENETICS　67　(4)　291-291　2000/10

    ISSN： 0002-9297

  245. 小児の喘息とアトピー性皮膚炎の遺伝的背景

    鈴木 洋一, 青木 洋子, 呉 繁夫, 松原 洋一, 成澤 邦明, 大浦 敏博, 平塚 真弘, 水柿 道直, 遠藤 廣子, 高柳 玲子

    日本小児アレルギー学会誌　14　(3)　390-390　2000/10

    Publisher: 日本小児アレルギー学会

    ISSN： 0914-2649

    eISSN： 1882-2738

  246. 喘息・アトピー性皮膚炎の遺伝的背景の解析

    鈴木 洋一, 青木 洋子, 呉 繁夫, 松原 洋一, 成澤 邦明, 大浦 敏博, 平塚 真弘, 水柿 道直, 遠藤 廣子, 高柳 玲子

    日本小児科学会雑誌　104　(10)　1061-1061　2000/10

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  247. 日本人ホロカルボキシラーゼ合成酵素欠損症患者のハプロタイプ

    鈴木 洋一, 楊 雪, 李 雪, 坂本 修, 青木 洋子, 平塚 真弘, 成澤 邦明

    ビタミン　74　(4)　231-231　2000/04

    Publisher: (公社)日本ビタミン学会

    ISSN： 0006-386X

  248. 日本人ホロカルボキシラーゼ合成酵素欠損症患者のハプロタイプ

    楊 雪, 鈴木 洋一, 李 雪, 坂本 修, 青木 洋子, 平塚 真弘, 成澤 邦明

    日本先天代謝異常学会雑誌　15　(2)　207-207　1999/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  249. 高グリシン血症モデル・マウス ドミナント・ネガティブ変異の過剰発現による機能的ノックアウト

    呉 繁夫, 新家 利一, 坂田 芳之, 青木 洋子, 松原 洋一, 成澤 邦明

    日本先天代謝異常学会雑誌　15　(2)　251-251　1999/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  250. ホロカルボキシラーゼ合成酵素欠損症の臨床像と遺伝子型

    鈴木 洋一, 坂本 修, 李 雪, 楊 雪, 青木 洋子, 平塚 真弘, 成澤 邦明, 工藤 純, 清水 信義

    ビタミン　73　(5〜6)　330-330　1999/06

    Publisher: (公社)日本ビタミン学会

    ISSN： 0006-386X

  251. ホロカルボキシラーゼ合成酵素欠損症の臨床像の多様性と遺伝子変異

    鈴木 洋一, 坂本 修, 李 雪, 楊 雪, 青木 洋子, 平塚 真弘, 成澤 邦明, 工藤 純, 清水 信義

    ビタミン　73　(4)　264-264　1999/04

    Publisher: (公社)日本ビタミン学会

    ISSN： 0006-386X

  252. ホロカルボキシラーゼ合成酵素欠損症の臨床像の多様性と遺伝子変異

    鈴木 洋一, 坂本 修, 李 雪, 青木 洋子, 平塚 真弘, 工藤 純, 清水 信義, 成澤 邦明

    日本先天代謝異常学会雑誌　14　(2)　219-219　1998/10

    Publisher: 日本先天代謝異常学会

    ISSN： 0912-0122

  253. Mechanism of biotin responsiveness in holocarboxylase synthetase deficiency

    SAKAMOTO O, AOKI Y, LI X, SUZUKI Y, HIRATSUKA M, NARISAWA K

    13　(3)　474-474　1997/10/15

    ISSN： 0912-0122

  254. Identification of human holocarboxylase synthetase (HCS) proteins

    HIRATSUKA M, SAKAMOTO O, LI X, SUZUKI Y, AOKI Y, NARISAWA K

    13　(3)　473-473　1997/10/15

    ISSN： 0912-0122

  255. A case of holocarboxylase synthetase deficiency with mild clinical phenotype : enzymatic and molecular analysis

    SAKAMOTO O, AOKI Y, SUZUKI Y, HIRATSUKA M, LI X, CHIKAOKA H, TAKITA S, NARISAWA K

    12　(2)　254-254　1996/10/15

    ISSN： 0912-0122

  256. ホロカルボキシラ-ゼ合成酵素(HCS)欠損症の遺伝子異常と遺伝子診断

    成沢 邦明, 鈴木 洋一, 青木 洋子

    日本臨床　54　(1)　259-267　1996/01

    Publisher: 日本臨床社

    ISSN： 0047-1852

  257. [Cloning of the holocarboxylase synthetase cDNA and identification of mutations prevalent in Japanese HCS-deficient patients] (Nippon Rinsho)

    Narisawa K, Suzuki Y, Aoki Y

    Nippon Rinsho　54　(1)　259-267　1996/01

  258. 6.ホロカルボキシラーゼ合成酵素欠損症の遺伝子解析とその臨床応用 : ビタミンB研究委員会 第344回会議研究発表要旨

    成澤 邦明, 鈴木 洋一, 青木 洋子

    ビタミン　69　(5)　329-330　1995/06/25

    Publisher: 日本ビタミン学会

    ISSN： 0006-386X

  259. 7.ホロカルボキシラーゼ合成酵素欠損症の分子遺伝学 : ビタミンB研究委員会 : シンポジウム(平成5年度) : ビオチン研究の進歩

    成澤 邦明, 鈴木 洋一, 千葉 靖, 青木 洋子, 石田 義則

    ビタミン　68　(5)　320-321　1994/06/25

    Publisher: 日本ビタミン学会

    ISSN： 0006-386X

  260. Association between a polymorphism of the 65K-glutamate decarboxylase gene and insulin-dependent diabetes mellitus.

    呉繁夫, 青木洋子, 成沢邦明, 佐藤譲, 大和田操, 川村智行, 一色玄

    日本先天代謝異常学会雑誌　10　(2)　1994

    ISSN： 0912-0122

  261. 7.ホロカルボキシラーゼ合成酵素cDNAのクローニング : ビタミンB研究委員会第334回会議研究発表要旨

    成澤 邦明, 鈴木 洋一, 千葉 靖, 石田 義則, 青木 洋子, 岩松 明彦

    ビタミン　67　(8)　441-441　1993/08/25

    Publisher: 日本ビタミン学会

    ISSN： 0006-386X

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Books and Other Publications 6

  1. The RASopathies

    Yoko Aoki, Tetsuya Niihori

    Springer　2024/11

  2. 助産基礎教育テキスト 第2巻 ウィメンズヘルスケア

    吉沢, 豊予子

    日本看護協会出版会　2023/10

    ISBN: 9784818026124

  3. がんゲノム医療やさしい系統講義

    松浦, 成昭, 櫻井, 晃洋, 石岡, 千加史, 西尾, 和人, 全国がんプロ協議会

    メディカル・サイエンス・インターナショナル　2023/04

    ISBN: 9784815730727

  4. 新遺伝医学やさしい系統講義19講

    福嶋, 義光, 櫻井, 晃洋, 古庄, 知己

    メディカル・サイエンス・インターナショナル　2019/09

    ISBN: 9784815701666

  5. 症候群ハンドブック

    井村裕夫, 青木洋子

    中山書店　2011/05/09

  6. Inborn Errors of Development 2nd ed.

    Epstein C. Eickson R, Wynshaw-Boris A ed, 青木洋子, 松原洋一

    Oxford University Press　2008/03/01

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Presentations 56

  1. 次世代シークエンサーを用いた希少遺伝性疾患の原因解明と遺伝子診断の現状

    日本人類遺伝学会第58回大会　2013/11/20

  2. 遺伝カウンセリングとは

    平成25年度東北大学病院がんセミナー　2013/08/08

  3. Genetic syndromes associated with the Ras/MAPK pathway and the identification of mutations in a new gene, RIT1, for Noonan syndrome. International-presentation

    Niihori Y, Inoue S, Matsubara Y

    Third International Meeting on Genetic Syndromes of the Ras/MAPK Pathway:Towards a Therapeutic Approach　2013/08/02

  4. 神経-心奇形連鎖：Noonan症候群類縁疾患における、RAS-MAPKシグナル伝達経路の関与

    第55回日本小児神経学会学術集会　2013/05/30

  5. 次世代シークエンサーを用いたヌーナン症候群の遺伝子診断と新規原因遺伝子検索

    第116回日本小児科学会学術集会　2013/04/19

  6. ヌーナン症候群とその類縁疾患の遺伝子診断

    第46回日本小児内分泌学会学術集会　2012/09/27

  7. Update on RASopathy mutation analysis and epidemiology in Japan. International-presentation

    4th International Meeting on Rare Disorders of the RAS-MAPK Pathway　2012/07/22

  8. Genetic syndromes associated with the Ras/MAPK pathway International-presentation

    Yoko Aoki

    The 11 th East Aian Union of Human Genetics (EAUHGS) Annual Meeting　2011/11/09

  9. コステロ症候群の遺伝子解析およびHRAS変異体の機能解析

    新堀哲也, 青木洋子, 岡本伸彦, 黒澤健司, 大橋博文, 水野誠司, 川目裕, 松原洋一

    日本人類遺伝学会第56回大会　2011/11/09

  10. コステロ症候群・CFC症候群の全国実態調査とその病態に関する研究

    阿部裕, 青木洋子, 栗山進一, 川目裕, 岡本伸彦, 黒澤健司, 大橋博文, 水野誠司, 緒方勤, 呉繁夫, 新堀哲也, 松原洋一

    日本人類遺伝学会第56回大会　2011/11/09

  11. Epidemiological features of Costello Syndrome and Cardio-facio-cutaneous Syndrome: findings from the first nationwide survey. International-presentation

    Y. Abe, Y. Aoki, S. Kuriyama, H. Kawame, N. Okamoto, K. Kurosawa, H. Ohashi, S. Mizuno, T. Ogata, S. Kure, T. Niihori, Y. Matsubara

    12th International Congress of Human Genetics　2011/10/11

  12. HRAS mutants identified in Costello syndrome patients have the ability to induce cellular senescence: possible association with the pathogenesis of Costello syndrome. International-presentation

    T. Niihori, Y. Aoki, N. Okamoto, K. Kurosawa, H, e

    12th International Congress of Human Genetics　2011/10/11

  13. Identification of a susceptibility gene for Moyamoya disease, RNF213 by a genome-wide association study. International-presentation

    S. Kure, F. Kamada, Y. Aoki, Y. Abe S, Komatsuzaki, A. Kikuch, J.Kanno, T. Niihori, M. Fuji-mura, Y. Mashimo, M. Ono, N. Ishii, Y. Owada, Y. Suzuki, A. Hata, T. Tominaga, Y. Matsubara

    12th International Congress of Human Genetics　2011/10/11

  14. コステロ症候群の遺伝子解析およびHRAS変異体の機能解析

    新堀哲也, 青木洋子, 阿部裕, 斎藤由佳, 小松崎匠子, 松原洋一

    第114回日本小児科学会学術集会　2011/08/12

  15. 5番染色体短腕部分欠失にマーカー染色体を伴う染色体異常が検出された一例

    番染色体短腕部分欠失にマーカー染色体を伴う染色体異常が検出された一例

    第114回日本小児科学会学術集会　2011/08/12

  16. MEK1遺伝子の変異を認めたLEOPARD症候群の男児例

    西 恵理子, 村松 友佳子, 谷合 弘子, 水野 誠司, 斎藤 由佳, 青木 洋子, 松原 洋一

    日本小児遺伝学会　2011/08/11

  17. Epidemiological Features of Costello and CFC Syndromes International-presentation

    Aoki Y, Matsubara Y

    International meeting on genetic syndromes of the Ras/MAPK pathway　2011/07/29

  18. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome International-presentation

    Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara

    International meeting on genetic syndromes of the Ras/MAPK pathway　2011/07/29

  19. Epidemiological features of Costello Syndrome and Cardio-facio-cutaneous Syndrome: findings from the first nationwide survey. International-presentation

    Y. Abe, Y. Aoki, S. Kuriyama, H. Kawame, N. Okamoto, K. Kurosawa, H. Ohashi, S. Mizuno, T. Ogata, S. Kure, T. Niihori, Y. Matsubara

    International meeting on genetic syndromes of the Ras/MAPK pathway　2011/07/29

  20. Hematologic abnormalities associated with patients with cardio-facio-cutaneous syndrome. International-presentation

    Yuka Saito, Yoko Aoki, Tetsuya Niihori, Akira Ohtake, Atsushi Shibuya, Kazuhito Sekiguchi, So-ichi Suenobu, Taturo Izumi, Hideki Muramatsu, Seiji Kojima, Shigeo Kure, Shigeru Tsuchiya, Yoichi Matsubara

    International meeting on genetic syndromes of the Ras/MAPK pathway　2011/07/29

  21. コステロ症候群・CFC症候群の全国実態調査とその病態に関する研究

    松原洋一, 阿部裕, 新堀哲也, 黒澤健司, 岡本伸彦, 水野誠司, 大橋博文, 川目裕, 緒方勤, 呉繁夫, 栗山進一, 青木洋子

    日本遺伝子診療学会 (遺伝医学合同学術集会2011)　2011/06/16

  22. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation International-presentation

    Yoko Aoki, Tomoko Kobayashi, Tetsuya Niihori, Yoichi Matsubara

    1st international symposium on carcinogenic spiral &9th international conference on protein phosphatase　2011/02/01

  23. SHOC2 mutation analysis in Noonan-like syndrome and hematologic malignancies International-presentation

    S. Komatsuzaki, Y. Aoki, T. Niihori, N. Okamoto, R.CM. Hennekam, S. Hopman, H. Ohashi, S. Mizuno, Y. Watanabe, H. Kamasaki, I. Kondo, N. Moriyama, K. Kurosawa, H. Kawame, M. Imaizumi, T. Rikiishi, S. Tsuchiya, S. Kure, Y. Matsubara

    第60回アメリカ人類遺伝学会　2010/11/02

  24. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan Y International-presentation

    Abe, Y. Aoki, T. Niihori, H. Ohashi, K. Kurosawa, N. Okamoto, H. Kawame, S. Mizuno, T. Ogata, S. Kuriyama, S. Kure, Y. Matsubara

    第60回アメリカ人類遺伝学会　2010/11/02

  25. Hematologic abnormalities associated with patients with cardio-facio-cutaneous syndrome. International-presentation

    Yuka Saito, Yoko Aoki, Tetsuya Niihori, Akira Ohtake, Atsushi Shibuya, Kazuhito Sekiguchi, So-ichi Suenobu, Taturo Izumi, Hideki Muramatsu, Seiji Kojima, Shigeo Kure, Shigeru Tsuchiya, Yoichi Matsubara

    第60回アメリカ人類遺伝学会　2010/11/02

  26. Noonan症候群類縁疾患および血液腫瘍細胞におけるSHOC2遺伝子変異解析

    小松崎匠子, 青木洋子, 新堀哲也, 岡本伸彦, 大橋博文, 水野誠司, 渡辺順子, 近藤郁子, 黒澤健司, 川目裕, 今泉 益栄, 力石健, 土屋滋, 呉繁夫, 松原洋一

    日本人類遺伝学会第55回大会　2010/10/27

  27. Noonan症候群類縁疾患におけるRAF1遺伝子解析とその発症メカニズムの検討

    松原洋一, 小林朋子, 新堀哲也, 呉繁夫, 青木洋子

    第17回日本遺伝子診療学会大会　2010/08/05

  28. RASシグナル伝達異常と先天奇形症候群

    青木洋子, 新堀哲也, 松原洋一

    第113回日本小児科学会学術集会　2010/04/23

  29. Noonan症候群類縁疾患におけるRAF1遺伝子解析とその発症メカニズムの解明

    小林朋子, 青木洋子, 新堀哲也, 鳴海洋子, 小松崎匠子, 土屋滋, 呉繁夫, 松原洋一

    第113回日本小児科学会学術集会　2010/04/23

  30. 腫瘍を合併する先天奇形症候群の分子メカニズム

    青木洋子, 松原洋一

    第71回日本血液学会学術集会　2009/10/23

  31. CFC Syndrome with BRAF mutation at exon 15 in a patient with marked cutaneous symptoms International-presentation

    E. Nishi, S. Mizuno, T. Niihori, Y. Aoki, Y. Matsubara

    59回アメリカ人類遺伝学会　2009/10/20

  32. Noonan症候群類縁疾患(The RAS/MAPK syndromes)の包括的遺伝子解析

    小林朋子, 青木洋子

    日本人類遺伝学会第54回大会　2009/09/23

  33. Molecular analysis and long-term follow-up study in Noonan syndrome and related disorders. International-presentation

    Kobayashi T, Aoki Y, Niihori T, Komatsuzaki S, Kure S, Matsubara Y

    Genetic Syndromes of the RAS/MAPK Pathway: From Bedside to Bench and Back　2009/08/01

  34. ホロカルボキシラーゼ合成酵素欠損症の確定診断法の変遷

    鈴木洋一, 真下陽一, 青木洋子, 松原洋一, 羽田明

    第16回日本遺伝子診療学会大会　2009/07/31

  35. Noonan症候群類縁疾患(The RAS/MAPK syndromes)の包括的遺伝子解析

    青木洋子, 新堀哲也, 小林朋子, 松原洋一

    第16会日本遺伝子診療学会大会　2009/07/30

  36. RAF１遺伝子変異を同定したNoonan症候群３例の臨床像

    岡本伸彦, 松田圭子, 秋丸憲子, 青木洋子, 小林朋子, 松原洋一

    第16回日本遺伝子診療学会大会　2009/07/30

  37. Mutation database of Noonan, Costello and cardio-facio-cutaneous (CFC) syndromes International-presentation

    Y. Aoki, T. Niihori, T. Kobayashi, S. Kure, Y. Matsubara

    European Humen Genetics Conference 2009　2009/05/23

  38. チロシンホスファターゼ・Rasシグナル異常と先天性疾患

    青木洋子

    第31回日本分子生物学会年会、第81回日本生化学会合同大会　2008/12/09

  39. The Ras/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders International-presentation

    青木洋子

    8th International Conference on Protein Phosphatases　2008/11/12

  40. 先天異常症と随伴腫瘍の統合的ゲノム解析

    青木洋子, 松原洋一

    第67回日本癌学会学術総会　2008/10/28

  41. 先天異常症と随伴腫瘍の病態解析

    青木洋子

    日本人類遺伝学会 第53回大会　2008/09/27

  42. The RAS/MAPK syndromes: Novel roles of the RAS pathway in human genetic disorders International-presentation

    松原洋一, 青木洋子

    The 2008 EAUHGS Symposium and the 8th EAUHGS Annual Meeting　2008/07/19

  43. HRAS International-presentation

    青木洋子

    ヨーロッパ人類遺伝学会サテライトミーティング　2008/05/30

  44. RAS変異と奇形症候群

    青木洋子

    日本小児血液学会・日本小児癌学会　2007/12/14

  45. Novel Roles of the RAS pathway in human development: Germline mutations in RAS cause congenital anomaly syndromes

    Yoko Aoki, Yoichi Matsubara

    日本癌学会　2007/10/05

  46. HRAS Gene: Structure & Function International-presentation

    青木洋子

    NIH-sponsored 「The 1st International Costello Syndrome Research Symposium」　2007/07/20

  47. Discovery of genes for Costello syndrome and CFC syndrome and comprehensive mutation analysis of Noonan, Costello and CFC patients International-presentation

    Y. Aoki, T. Niihori, Y. Narumi, H. Kawame, K. Kurosawa, H. Ohashi, M. Filocamo, G. Neri, H. Cav&eacute, A. Verloes, N. Okamoto, R.C.M Hennekam, G. Gillessen-Kaesbach, D. Wieczorek, M.I.Kavamura, L. Wilson, Y. Suzuki, S. Kure, Y. Matsubara

    NIH-sponsored international scientific meeting「Cardiofaciocutaneous Syndrome and Noonan Syndrome Scientific Meeting 2006」　2006/11/17

  48. RAS/MAPKシグナル伝達系異常による先天奇形症候群の分子遺伝学的研究

    青木洋子

    第51回人類遺伝学会　2006/10/12

  49. Comprehensive mutation analysis in Costello syndrome, CFC syndrome and Noonan syndrome : clinical and genetic overlap among three disorders International-presentation

    Plenary)Y Aoki, T. Niihori, Y. Narumi, H. Kawame, K. Kurosawa, H. Ohashi, M. Filocamo, G. Neri, H. Cav&eacute, A. Verloes, N. Okamoto, R.C.M Hennekam, G. Gillessen-Kaesbach, D. Wieczorek, M.I.Kavamura, L. Wilson, Y. Suzuki, S. Kure, Y. Matsubara

    The American Society of Human Genetics 56th Annual Meeting　2006/10/09

  50. RAS/MAPKシグナル伝達系異常による先天奇形症候群の分子遺伝学的研究

    青木洋子

    群馬大学21世紀COE若手研究者シンポジウム　2006/10/04

  51. Germline mutations of proto-oncogenes in the RAS-RAF-ERK pathway cause Costello syndrome and International-presentation

    Yoihci Matsubara, Yoko Aokiら

    European Human Genetics Coonference 2006　2006/03/09

  52. 腫瘍好発性先天奇形症候群の遺伝学的研究について

    青木洋子

    第９回東北家族性腫瘍研究会　2006/01/28

  53. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome International-presentation

    新堀哲也, 青木洋子ら

    米国人類遺伝学会　2005/10/25

  54. ヌーナン症候群の酵素活性測定による診断法の確立

    新堀哲也, 青木洋子

    第50回人類遺伝学会　2005/09/20

  55. ヌーナン症候群と小児白血病の遺伝子解析と変異蛋白の生化学的解析

    新堀哲也, 青木洋子ら

    第49回人類遺伝学会　2004/10/12

  56. ヌーナン症候群とJMMLの遺伝子解析と変異蛋白の生化学的解析

    優秀演題賞, 青木洋子ら

    日本小児科学会　2004/04/09

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Research Projects 30

  1. 骨髄不全を伴う先天性症候群の病態解析

    新堀 哲也, 青木 洋子, 井上 晋一

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2025/04 - 2028/03

  2. Elucidation of novel mechanisms of RASopathies

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  3. Elucidation of novel mechanisms of RASopathies

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  4. Pathogenesis and development of gene therapy for rare genetic disorders focusing on proteostasis of the RAS-GTPase

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  5. Elucidation of pathogenesis and development of new treatment for refractory vascular malformation syndrome by genetic analysis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2022/04/01 - 2025/03/31

  6. Lymphatic abnormalities in RAS related disorders

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2021/07/09 - 2024/03/31

  7. がん遺伝子産物RASに対する分解誘導戦略の構築

    阿部 太紀, 新堀 哲也, 吉成 浩一, 青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    2020/04/01 - 2023/03/31

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    RASファミリーには、多数のサブファミリーとその変異型が数多く存在する。そのため、疾患の原因となる多種多様なRAS分子に効果を有する汎用性、特定のRAS変異体のみを標的とする分子特異性、を状況に応じて選択可能なRAS標的薬の開発が不可欠である。そこで３年計画の初年度である本年度は、LZTR1のRAS選択性検討、各種変異体に対するRAS分解作用の検討、in vivoならびにin vitro系の構築を中心に計画を実行した。具体的には以下の通りである。 LZTR1のRAS分子選択性を明らかにするためにLZTR1欠損細胞をゲノム編集により作出し、当該細胞とその親株を使用してマルチオミックス解析（トランスクリプトーム解析、プロテオーム解析）を実施した。その結果、LZTR1の欠損によって顕著に発現量が増加するするRAS分子を数種類に絞り込むことに成功し、ウェスタンブロットならびにRT-qPCRによりマルチオミックス解析結果を検証した。 培養細胞を用いた実験系において、RAS変異体発現プラスミドを約20種類作成し、野生型LZTR1発現プラスミドとRAS変異体発現プラスミドのco-transfection実験を実施することでLZTR1により分解可能なRAS変異体を特定すると共に、野生型LZTR1では分解不可能なRAS変異体が存在することを明らかにした。さらに、既知のLZTR1病的バリアントより優性遺伝、劣性遺伝形式と考えられる遺伝子バリアントをそれぞれ約10種類選択し、LTR1変異体発現プラスミドを作成しRAS分解能の有無をco-transfection実験により解析した。 さらに、CRISPR/Cas9システムを使用したゲノム編集によるLZTR1遺伝子改変モデル生物の樹立を試みた。その結果、複数の生物種において病的バリアントまたはLZTR1単純欠損モデルの樹立に成功した。

  8. New mechanisms and pathogenesis of Noonan syndrome adn related disorders

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2020/04/01 - 2023/03/31

  9. Pathophysiological analysis of radioulnar synostosis with or without amegakaryocytic thrombocytopenia

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2020/04/01 - 2023/03/31

  10. Crosstalk between mechanism of metabolic abnormalies in congenital disorders and cancer cell metabolism

    Aoki Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2018/06/29 - 2021/03/31

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    Costello syndrome is involved in RASopathies. We have generated Costello syndrome model mice and found that the mutant mice are resistant to high-fat diet-induced obesity. Histology of liver showed microvesicular hepatic steatosis, suggesting abnormal beta-oxidation. In this study, we comprehensively analyzed glycolysis, gluconeogenesis, lipid metabolism, nucleic acid, and amino acid metabolism in addition to the revealed mitochondrial β-oxidation pathway in the liver. In mutant mice, the blood glucose level decreased and the expression of β-oxidation-related genes decreased. In addition, glycolysis and cholesterol synthesis are enhanced with increased glucagon levels, which is a hormone that regulates blood glucose level. Gluconeogenesis is decreased despite high glucagon. Surprisingly, however, changes in the expression of these genes involved in energy metabolism were not observed at all after fasting.

  11. CFC症候群の心疾患におけるヒストン修飾の役割の解明

    井上 晋一, 新堀 哲也, 青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2018/04/01 - 2021/03/31

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    Cardio-facio-cutaneous (CFC)症候群は心疾患、特異的顔貌、皮膚疾患、精神発達遅滞を示す遺伝性難病で、その原因遺伝子は癌原遺伝子BRAFである。我々はこれまでにCFC症候群モデルマウス(Brafノックイン（KI）マウス)を作製しCFC症候群患者同様に心疾患を示すこと、またこの心疾患治療にはヒストンH3K27脱メチル化酵素阻害剤(GSK-J4)、MEK阻害剤が有用であることを報告した。本研究では、なぜGSK-J4がBraf KIマウスの心疾患改善に有用であるのか、RAS/MAPKシグナルとヒストン修飾に焦点をあて解析を行った。本年度はBraf KIマウスの心臓発生期において発現変動する遺伝子を同定するためマイクロアレイ解析を行い、その後、定量的リアルタイムPCRによって再現性の確認を行った。その結果、Braf KIマウス胎仔心臓においてNppa, Nppb, Six1など心疾患・心臓発生に重要な遺伝子が発現変動していることを発見した。さらにBraf KIマウス胎仔の抽出液ではH3K27me1タンパク発現量が変化していることを見出した。 上記の実験に加え、RASサブファミリーであるRit1（RAS-like without CAAX1）遺伝子変異を持つノックインマウス（Rit1 KI: CFC症候群と類似した疾患であるヌーナン症候群モデルマウス）を新たに作製した(Takahara et.al, EBioMedicine, 2019)。RIT1タンパク質はBRAFタンパクの上流にあり、特にBRAFと相互的な関係性が強いとされている。よってRit1 KIマウスを新たに追加し、包括的にRAS/MAPK経路とヒストン修飾との関係性について解析を始めた。

  12. Functional analysis of mutants of EVI1 identified in individuals with radioulnar synostosis with amegakaryocytic thrombocytopenia

    Niihori Tetsuya

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2017/04/01 - 2020/03/31

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    We sequenced MECOM, HOXA11, SMAD6, and NOG of DNA from patients with radioulnar synostosis with or without thrombocytopenia and identified several rare variants. The significance of these variants are needed to be determined. We observed phenotypic changes in the mecom knockdown zebrafish by morpholino in a dose-dependent manner.The mecom knockout zebrafish were also generated and analyzed.

  13. Functional analysis and modeling in RASopathies

    Aoki Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2017/04/01 - 2020/03/31

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    RASopathies are a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the Ras/MAPK signaling pathway. In this project, w provided genetic analysis to patients with RASopathies and identified a novel gene, RRAS2, in Noonan syndrome patients (Niihori et al, Am J Hum Genet, 2019). Detailed clinical manifestations were evaluated in LZTR1 mutation-positive patients (Umeki I et al. Hum Mutat 2019). We demonstrated that LZTR1 associates with PPP1B-RAF1-SHOC2 complex. Although function in LZTR1 has not been clarified, we identified that LZTR1 facilitates polyubiquitination and degradation of RAS (Abe T et al. Cell Death Differ. 2020). We also showed that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction.

  14. Metablic alterarion and growth control in congenital anomaly syndrome

    Aoki Yoko, OBA Daiju, NISHIYAMA Ayumi, UMEKI Ikumi, TAKAHARA Shingo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

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    To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (HrasG12S/+ mice) as a mouse model of Costello syndrome. On a high-fat diet, HrasG12S/+ mice developed a lean phenotype with microvesicular hepatic steatosis, resulting in early death compared with wild-type mice. Under starvation conditions, hypoketosis and elevated blood levels of long-chain fatty acylcarnitines were observed, suggesting impaired mitochondrial fatty acid oxidation. Our findings suggest that the oncogenic Hras mutation modulates energy homeostasis in vivo.

  15. Establishment of comprehensive gene analysis of Noonan syndrome and related disorders

    Niihori Tetsuya, Umeki Ikumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    NGS enables comprehensive gene analysis of Noonan syndrome and related disorders. However, there are problems about cost and flexibility of target design. To solve these problems, we established a gene analysis system using multiplex PCR and NGS. We analyzed total 48 samples including positive controls. The results were acceptable, though minor modifications were needed.

  16. Molecular analysis and pathogenesis of the RAS/MAPK syndromes

    Aoki Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    We have performed genetic testing in patients with RASopathies and successfully identified a new gene, RIT1, in patients with Noonan syndrome. In this study, we further analyzed clinical manifestations in RIT1 mutation-positive patients and performed functional analysis in cell culture system. We developed comprehensive analysis system using a next generation sequencer to analyze genes for RASopathies. We successfully generated model mice for CFC syndrome. The results would lead to the understanding of the pathogenesis of these disorders and the development of therapeutic means.

  17. Epigenomic regulation in congenital anomaly syndromes

    Aoki Yoko, MATSUBARA Yoichi, NIIHORI Tetsuya, INOUE Shinichi, YAOITA Masako, OBA Daiju, NISHIYAMA Ayumi, UMEKI Ikumi, TAKAHARA Shingo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    In this study, we analyzed genes that are associated with epigenetic modifications in patients, who are clinically diagnosed as having RASopathies, and identified pathogenic mutations in three affected individuals. We generated a knock-in mice expressing a Braf p.Q241R mutation, as a model mice for CFC syndrome. Treatment with a MEK inhibitor, PD0325901, and a histone H3K27 demethylase inhibitor, GSK-J4, have rescued embryonic lethality in BrafQ241R/+ mice. To explore the mechanisms of efficacy in PD0325901 and GSK-J4 co-treatment, we examined mRNA and protein levels of histone H3K27 methylase and histone H3K27 demethylases in heart tissues from control and BrafQ241R/+ embryos. Further analysis on methylation profiling of H3K27 in each gene will clarify the mechanisms why co-treatment of PD0325901 and GSK-J4 rescued the embryonic lethality in in BrafQ241R/+ mice.

  18. Identification of pathogenic genes for genetic diseases using next-generation sequencing and high-density microarray

    MATSUBARA Yoichi, NIIHORI Tetsuya, KURE Shigeo, AOKI Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2011 - 2012

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    Next-generation sequencing and high-density microarray analysis were used to investigate disease-causing genes for genetic diseases in which molecular pathogenesis had not been clarified. We successfully identified a pathogenic gene for a subtype of myopathies in one family. We also identified novel disease-causing genes in a congenital anomaly syndrome and an endocrine disorder. The results would lead to the understanding of the pathogenesis of these disorders and the development of therapeutic means.

  19. Novel functions of proto-oncogenes in human development

    AOKI Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (S)

    Institution: Tohoku University

    2007 - 2011

  20. Molecular analysis of congenital anomaly syndromes caused by impaired intracellular signaling pathways

    MATSUBARA Yoichi, KURE Shigeo, AOKI Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2008 - 2010

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    We have collected DNA samples from 350 patients with Noonan syndrome, Costello syndrome or CFC syndrome and performed mutation analysis of nine disease-causing genes including a novel gene. Genotype-phenotype correlations were observed. We revealed molecular pathogenesis of RAF1 mutations. Model mice were successfully generated.

  21. 癌遺伝子関連ゲノム情報を活用した先天奇形症候群原因遺伝子の同定

    松原 洋一, 青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2008 - 2009

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    本研究の目的は、従来、体細胞変異が数多く検出されている癌遺伝子およびそのシグナル伝達経路関連遺伝子を候補とし、先天奇形症候群の病因遺伝子を同定するための戦略について検討と実証をおこなうこと、さらに癌原遺伝子を生殖細胞変異にもつ患者における発癌のメカニズムを明らかにすることである。まず、選定した候補遺伝子について、症例より得られた検体を対象に、順次、遺伝子変異の検索を行った。またシークエンスにより遺伝子変異が認められなかった症例については、MLPA法を用いて候補遺伝子のコピー数の増減の有無を検索した。その結果、RAS/MAPK症候群の原因遺伝子としてあらたにRAF1およびSHOC2が同定された。つぎに、変異蛋白の細胞内発現による機能解析を実施した。まず、ヌーナン症候群の患者18人で見出したRAF1遺伝子変異について、臨床症状との相関と変異蛋白の機能解析をおこなった。RAF1遺伝子変異を持つ場合、PTPN11やSOS1などの他の遺伝子異常に比べて肥大型心筋症と低身長の合併頻度が有意に高かった。変異RAF1蛋白の機能解析では、抑制性のS259部位のリン酸化が低下しており、そのためにRAF1活性抑制に重要な14-3-3蛋白との結合が低下し、非刺激時にも下流のERKを活性化していることが明らかとなった。一方、SHOC2遺伝子変異を有している患者は11人同定され、詳細な解析を実施中である。コピー数多型(CNV)の探索のために、DNAマイクロアレイシステムを立ち上げ、患者での検索を開始した。

  22. シグナル伝達マップ作成とプロテオーム解析による先天奇形症候群の病因遺伝子探索

    松原 洋一, 青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 東北大学

    2007 - 2008

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    申請者らは2005年にHRASの生殖細胞系列での変異を先天奇形症候群であるCostello症候群で同定した(Aoki et.al., Nature Genetics, 2005)。また2006年にcarcio-facio-cutaneous(CFC)症候群の原因がKRAS, BRAFの遺伝子変異が原因であることを報告した(Niihori, Aoki et.al. Nature Genetics, 2006)。申請者らの発見がブレークスルーとなり、RAS/MAPKに異常を持つ先天異常症という新しい疾患概念が確立した。本研究の目的は、これまでの細胞ベース・マウスベースとは異なる、ヒト発生異常の表現型の臓器別・stage別の詳細な情報と遺伝子の機能・シグナル伝達マップを包括的に網羅するヒト発生異常のデータベースを構築し、データベースに基づいたプロテオーム解析(遺伝子発現タンパクの網羅的解析)をおこなうことによってMCA/MRの原因遺伝子を革新的な探索法を開発しようとするものである。申請者らは、これまでにNoonan類縁疾患250人を収集し既知の原因遺伝子PTPN11, HRAS, KRAS, BRAF, MEK1, MEK2の包括的遺伝子解析を行ってきた。今年度はPTPN11, HRAS, KRAS, BRAF, MEK1, MEK2陰性のNoonan症候群22家系とCFC症候群30人に対してSOS1遺伝子解析を行ったところ、3世代の家系を含むヌーナン症候群2家系とCFC症候群3人に遺伝子変異を同定した。ヌーナン症候群とその類縁疾患はシグナル伝達経路であるRAS/MAPK経路の異常により起こることが明らかになり、私達はこの新しい疾患概念をRAS/MAPK症候群と呼ぶことを提唱した総説を発表した。また遺伝子変異と表現型・シグナル伝達での役割を包括的に記したデータベースを構築中であり、その一部をホームページで公開を開始した。

  23. 癌遺伝子関連ゲノム情報を活用した先天奇形症候群原因遺伝子の同定

    松原 洋一, 青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2006 - 2008

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    本研究の目的は、先天奇形症候群の病因遺伝子を同定するため、これまで体細胞変異が数多く検出されている癌遺伝子およびそのシグナル伝達経路関連遺伝子を候補として探索する戦略について、その検討と実証をおこなうことにある。 1)遺伝子変異のスクリーニングおよび遺伝子のコピー数の検討(松原、青木) 新たな候補遺伝子における遺伝子変異の検索を行い、これまで報告されていない変異を同定した。また、シークエンスにより遺伝子変異が認められなかった症例について、MLPA法を用いた候補遺伝子のコピー数の検索をおこなったが、これまでのところコピー数の異常は同定されなかった。 2)変異蛋白の機能解析 (1)細胞内発現による変異蛋白の生化学的・細胞生物学的特性の検討(青木) 変異遺伝子を細胞内で発現させ、その変異蛋白の活性や他の分子との結合について検討した。 (2)細胞内発現によるシグナル伝達系に及ぼす影響の検討(青木) 上記の発現ベクターと共に、シグナル伝達系の下流にあたる転写因子の転写活性をルシフェラーゼ活性として測定し、変異蛋白がそのシグナル伝達系に及ぼす影響を検討した。 (3)変異蛋白を過剰発現させたトランスジェニックマウスの作製に関する検討(青木、松原) トランスジェニックマウス作成のためのベクター作成をおこなった。 なお、本研究は東北大学医学部倫理委員会の承認(承認番号#2001-217)を得ており、遺伝子解析研究は3省庁の「ヒトゲノム・遺伝子解析研究に関する倫理指針」に沿って行った。

  24. ヌーナン症候群類縁疾患の分子診断と臨床症状の検討による疾患概念の再構築

    青木 洋子, 松原 洋一

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2007 - 2007

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    Noonan症候群と類縁疾患は特徴的な顔貌、心疾患、骨格の異常、精神遅滞を主徴とする先天奇形症候群である。申請者らは最近、Costello症候群が、これまで癌遺伝子としてよく知られていたHRAS遺伝子の変異によるシグナル伝達異常症であることを世界に先駆けて報告した(Aoki, et. al. Nature Genetics 37:1038-1040,2005)。さらにcardio-facio-cutaneous(CFC)症候群の原因が同じシグナル伝達上の分子であるKRASとBRAFであることを明らかにした(Niihori, et. al. Nature Genetics 38:294-6,2006)。本研究はNoonan・Costello・CFC症候群3疾患の患者の原因遺伝子6個の網羅的遺伝子解析を行い、その分子診断結果と詳細な臨床的検討を元に疾患概念を再構築することを目的とした。 Noonan症候群50人、Costello症候群35人、CFC症候群59人においてPTPN11, HRAS, KRAS, BRAF, MEK1/2全6遺伝子をシークエンスしたところ、遺伝子診断率はNoonan症候群でPTPN11=42%、Costello症候群でHRAS=57%、CFC症候群でKRAS, BRAF, MEK1/2=61%であった。HRAS陰性のCostello症候群には非典型例が存在し、Costello症候群典型例でのHRAS陽性率は80%であった。分子診断によって初期診断が覆される例も存在したが、臨床症状の再検討によっても、分子診断から得られる診断に合致しないと考えられる症例も存在した。これら3疾患は疾患により腫瘍合併頻度や腫瘍発生部位が異なるため遺伝子診断は有用であるが、その臨床的・遺伝学的重複を考慮して診断と治療方針を決定していく必要があると考えた。

  25. Molecular analysis of congenital anomaly syndromes due to mutations in signal transduction pathways

    MATSUBARA Yoichi, KURE Shigeo, AOKI Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2006 - 2007

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    We have been searching for genetic abnormalities in multiple congenital anomalies/mental retardation syndromes. Recently we identified mutations in the Ras/MAPK signaling pathways among Noonan-related syndromes, namely Costello syndrome and cardiofaciocutaenous (CFC) syndrome. The purpose of the current study is to identify novel disease-causing genes related to various signal transduction pathways, to establish genetic testing protocols, and to perform functional studies to better understand the pathogenesis of these disorders. At first, we collected DNA samples and cell cultures from patients with Noonan syndrome, Costello syndrome, CFC syndrome and patients with similar clinical pictures. We performed comprehensive mutation analysis of the previously reported disease-causing genes and reported the results in a review in Human Mutation (Published Online: May 9 2008). Candidate gene analysis revealed mutations in novel genes. Functional studies of the identified mutations were performed to characterize their effects on the signaling pathway. We also started to create transgenic mice harboring mutated HRAS gene as a disease model for Costello syndrome. The entire study was approved by the Ethics Committee of Tohoku University School of Medicine and the genetic analysis was done according to the relevant guidelines.

  26. Identification of novel disease genes for Noonan-related syndromes

    AOKI Yoko, MATSUBARA Yoichi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2005 - 2006

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    Costello syndrome and CFC syndrome are rare, multiple congenital anomaly syndrome characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities and mental retardation. Clinical features with both syndromes overlap with those with Noonan syndrome. Gain-of-function mutations in PTPN11 have been identified in approximately 50% of individuals with clinically diagnosed Noonan syndrome(Tartaglia et al., 2001) SHP-2, the product of PTPN11, is a widely expressed cytoplasmic tyrosine phosphatase and has been implicated in signal transduction pathways elicited by growth factors, cytokines, hormones and extracellular matrix. No PTPN11 mutations have been found in individuals with Costello or CFC syndrome and genetic causes for these disorders had been unknown. We hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP-2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS (KRAS, HRAS and NRAS, as well as the recently identified ERAS genes) in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN//-negative Noonan syndrome. We discovered HRAS germline mutations in patients with Costello syndrome, a congenital anomaly/mental retardation syndrome (Aoki et al. 2005). This discovery provided a clue to identification of germline mutations in KRAS, BRAF and MAP2K1/2 mutations in patients with cardio-facio-cutaneous (CFC) syndrome (Niihori et al. 2006 and Narumi et al. 2007). These genes encode molecules in the RAS/RAF/MEK/ERK pathway, proposing a new concept that clinically related disorders, Noonan, Costello and CFC are caused by dys-regulation of RAS/RAF/MEK/ERK pathway.

  27. ヌーナン症候群の遺伝子解析とその成因についての分子遺伝学的研究

    青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 若手研究(B)

    Institution: 東北大学

    2003 - 2004

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    <目的>ヌーナン症候群は顔貌異常、翼状頸、低身長、心奇形、精神遅滞等を伴う症候群で、常染色体優性遺伝形式をとる。2001年にSH2 domain containing protein phosphatase SHP-2をコードするPTPN11遺伝子に遺伝子変異が同定された。報告では家族例と散発例を含めた約40%にアミノ酸置換を伴う遺伝子変異が同定された。これに引き続いて、小児白血病の一部にもSHP-2の変異が存在することが報告された。変異のうち5個はボスファターゼ活性の高いgain-of-function変異であることが証明されたが、ヌーナン症候群と白血病で同定される変異の機能的差異については明らかになっていない。 <結果と考察>日本人41人のヌーナン症候群と小児白血病29例でSHP-2遺伝子解析を行った。ヌーナン症候群では17人に1つの新しい変異と8種類の既知の変異が、小児白血病ではjuvenile myelomonocytic leukemia(JMML)1例、myelodysplastic syndrome1例、急性骨髄性白血病1例に2種類の変異がみつかった。2)ヌーナン症候群および小児白血病で同定した14変異のPTP活性測定では、野生型を1とした場合、変異では1.4-12.7倍と有意な活性上昇を示した。アミノ酸コドン61,71,72,76の変異の活性は他のコドンの変異よりも高く、活性の高いコドンに白血病での変異が集中していた。活性の高さと白血病の成因に関与がある可能性が認められた。3)HEK293細胞に2つの変異を発現させEGFで刺激した場合、予想に反してMAPキナーゼとc-fosのプロモーター活性は野生型cDNAを発現させた場合と比較して低下しており、活性化変異が必ずしも下流のシグナル活性化につながるわけではないことが明らかになった。

  28. DEVELOPMENT OF A NOVEL POINT-OF-CARE GENETIC TESTING METHOD

    MATSUBARA Youichi, KURE Shigeo, SUZUKI Youichi, AOKI Yoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: TOHOKU UNIVERSITY

    2003 - 2004

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    Clinical application of the genetic information to individual healthcare requires simple and rapid identification of nucleotide changes in clinical settings. We have devised a novel low tech method for the detection of a single nucleotide substitution using competitive allele-specific short oligonucleotide hybridization with immunochromatographic strip. The gene of interest is PCR amplified, hybridized to an allele-specific short oligonucleotide probe in the presence of a competitive oligonucleotide, and subjected to chromatography using a DNA test strip at room temperature. The genotype is unambiguously determined by the presence or the absence of visible purple lines on a strip. Feasibility of the method was demonstrated by the detection of a prevalent disease-causing mutations in a number of single-gene diseases and clinically important pramacogenetic polymorphisms. The procedure does not demand either technical expertise or expensive instruments and is readily performed in local clinical laboratories. The result is obtained within 10 minutes after PCR. The rapid and simple method may be used for point-of-care genetic diagnosis with potentially diverse clinical applications.

  29. チロシン脱リン化酵素SHP2の脳における機能について

    青木 洋子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 若手研究(B)

    Institution: 東北大学

    2001 - 2002

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    この研究の目的は、様々な増殖因子・サイトカイン・細胞接着物質等のシグナル伝達を制御するチロシン脱リン酸化酵素SHP-2の、脳神経幹細胞の増殖・分化とニューロンの生存における機能を明らかにすることである。このためCre/loxPシステムを用いて組織特異的にSHP-2のドミナントネガティブ変異(DN変異)を発現させるトランスジェニックマウスを作製した。 pCAGGSプロモーターの下流に、loxPに挟まれたEGFP(enhanced green fluorescent protein)を挿入し、その下流にDN変異を導入したコンストラクトを作製し、マウス受精卵に注入した。それを偽妊娠マウスの卵管に移植し全31匹の産子を得た。そのうちサザンブロットにて6ラインがトランスジェニックマウスであることが判明した。6ラインのうち3ラインは次世代でトランスジェニックマウスは生まれずその後の実験に用いることはできなかった。残りの3ラインを、主に神経、心臓、筋肉などにCreリコンビナーゼを発現しているpCAGGS-Creマウスをかけ合わせてその表現系を観察した。ライン#3-2:pCAGGS-Creをホモ接合体に持つマウスとかけ合わせたところ、3腹12匹のうち、ダブルトランスジェニックマウス(DN変異を発現)は1匹しか生まれず、多くが胎内で死亡している可能性が高い。ライン#7-5:ダブルトランスジェニックマウスはメンデルの法則にしたがって生まれてくるがオス3匹中1匹が3ケ月で死亡し(原因不明)、一匹に毛並み不良・外性器異常・手の筋力低下がみられている。ライン#8-4:ダブルトランスジェニックマウスのオス4匹中1匹に外性器異常がみられた。これまでの結果からSHP-2のDN変異を導入したマウスでは、原因はまだ不明であるが胎内/生後の死亡や外性器異常等が生じてくる可能性が高い。

  30. COMPREHENSIVE DNA DIAGNOSTIC SYSTEM FOR SINGILE GENE DISORDERS

    MATSUBARA Yoichi, AOKI Yoko, SUZUKI Yoichi, KURE Shigeo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: TOHOKU UNIVERSITY

    2001 - 2002

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    The purpose of the current study was to establish comprehensive DNA diagnostic system for various single gene disorders. To this end, we used a novel DNA test strip method to detect previously idertified pathogenic mutations. We also used denaturing high-performance liquid chromatography (DHPLC) to scan for unknown mutations and an automatic capillary DNA sequencer to confirm mutations. The DNA test strip method, originally developed in our laboratory, utilizes competitive allele-specific short oligonucleotide hybridization coupled with immunochromatographic strip. It was used for the detection of known mutations in glycogen storage disease type Ia and Ib, non-ketotic hyperglycinemia, aldehyde dehydrogenase 2 deficiency, Tay-Sachs disease, Gaucher disease, cyctic fibrosis, familial breast cancer due to BRCA1 or BRCA2 mutations, Factor V Leiden mutation, CYP2C19 and mitochondrial A1555G mutation. We also evaluated the feasibility of DHPLC followed by sequencing analysis from clinical diagnostic point of view. The combination of the three methods would facilitate DNA diagnosis by efficiently identifying mutations.

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  1. [日本国内] 第１回ヌーナン症候群シンポジウム

    2012/08/18 -

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    患者さん、ご家族、医療関係者の勉強と交流を目的とした会

  2. [日本国内] 第２回コステロ症候群・CFC症候群シンポジウム

    2011/09/19 -

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    患者さん、ご家族、医療関係者の勉強・交流を目的とした会

  3. [日本国内] コステロ症候群・CFC症候群シンポジウム

    2010/10/17 -

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    患者さん、ご家族、医療関係者の勉強・交流を目的とした会

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  1. 細胞内シグナル伝達異常による先天奇形症候群の病態解明と治療法開発の研究

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    細胞内シグナル伝達異常症の①臨床診断・遺伝子診断基盤の創生②新規原因遺伝子探索と生化学的解析③モデル生物とその治療薬の開発④患者・ご家族への情報提供を目的とする。

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  5. 成育希少疾患の症例登録と遺伝学的診断に関する研究

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  9. 分子診断に基づくヌーナン症候群の診断基準作成と新規病因遺伝子の探索

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  11. 小児白血病の原因究明に向けた基盤的研究

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    小児白血病の原因究明に向けた基盤的研究

  12. コステロ症候群・CFC症候群類縁疾患の診断基準作成と患者数把握に関する研究

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    全国調査と詳細な臨床症状の収集にによる診断基準作製研究

  13. 先天奇形症候群に合併する腫瘍の発生メカニズムの解明

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    先天奇形症候群に合併する腫瘍の発生メカニズムの解明

  14. ヌーナン症候群類縁疾患の分子遺伝学的診断法と遺伝子変異データベースの構築

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  15. 癌を合併する先天奇形症候群の病態の解明

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  16. ヌーナン症候群類縁疾患の分子遺伝学的診断法の確立と遺伝子変異データベースの構築

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