Details of the Researcher

PHOTO

Matsuyuki Shirota
Section
Graduate School of Medicine
Job title
Senior Assistant Professor
Degree

  • 博士（生命科学）（東京大学）

Professional Memberships 2

  • 日本蛋白質科学会

  • 日本生物物理学会

Research Areas 1

  • Life sciences / Morphology, anatomy / 生物情報学

Papers 87

  1. Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population. International-journal Peer-reviewed

    Kei-Ichiro Inamori, Katsuya Nakamura, Fumi Shishido, Jia-Chen Hsu, Masakazu Nagafuku, Takahiro Nitta, Junji Ikeda, Hidekane Yoshimura, Minori Kodaira, Naomi Tsuchida, Naomichi Matsumoto, Satoshi Uemura, Shiho Ohno, Noriyoshi Manabe, Yoshiki Yamaguchi, Akira Togayachi, Kiyoko F Aoki-Kinoshita, Shoko Nishihara, Jun-Ichi Furukawa, Tadashi Kaname, Masahiko Nakamura, Takayoshi Shimohata, Shu Tadaka, Matsuyuki Shirota, Kengo Kinoshita, Yutaka Nakamura, Isao Ohno, Yoshiki Sekijima, Jin-Ichi Inokuchi

    Frontiers in neuroscience　18　1437668-1437668　2024

    DOI： 10.3389/fnins.2024.1437668 　

    More details Close

    Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurological disorders that are characterized by progressive spasticity and weakness in the lower limbs. SPG26 is a complicated form of HSP, which includes not only weakness in the lower limbs, but also cognitive impairment, developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy, and is caused by biallelic mutations in the B4GALNT1 (beta-1,4-N-acetylgalactosaminyltransferase 1) gene. The B4GALNT1 gene encodes ganglioside GM2/GD2 synthase (GM2S), which catalyzes the transfer of N-acetylgalactosamine to lactosylceramide, GM3, and GD3 to generate GA2, GM2, and GD2, respectively. The present study attempted to characterize a novel B4GALNT1 variant (NM_001478.5:c.937G>A p.Asp313Asn) detected in a patient with progressive multi-system neurodegeneration as well as deleterious variants found in the general population in Japan. Peripheral blood T cells from our patient lacked the ability for activation-induced ganglioside expression assessed by cell surface cholera toxin binding. Structural predictions suggested that the amino acid substitution, p.Asp313Asn, impaired binding to the donor substrate UDP-GalNAc. An in vitro enzyme assay demonstrated that the variant protein did not exhibit GM2S activity, leading to the diagnosis of HSP26. This is the first case diagnosed with SPG26 in Japan. We then extracted 10 novel missense variants of B4GALNT1 from the whole-genome reference panel jMorp (8.3KJPN) of the Tohoku medical megabank organization, which were predicted to be deleterious by Polyphen-2 and SIFT programs. We performed a functional evaluation of these variants and demonstrated that many showed perturbed subcellular localization. Five of these variants exhibited no or significantly decreased GM2S activity with less than 10% activity of the wild-type protein, indicating that they are carrier variants for HSP26. These results provide the basis for molecular analyses of B4GALNT1 variants present in the Japanese population and will help improve the molecular diagnosis of patients suspected of having HSP.

  2. 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 　

    More details Close

    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.

  3. jMorp: Japanese Multi-Omics Reference Panel update report 2023. International-journal Peer-reviewed

    Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　2023/11/01

    DOI： 10.1093/nar/gkad978 　

    More details Close

    Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.

  4. Aurora A polyubiquitinates the BRCA1-interacting protein OLA1 to promote centrosome maturation. International-journal

    Zhenzhou Fang, Xingming Li, Yuki Yoshino, Moe Suzuki, Huicheng Qi, Hinari Murooka, Riko Katakai, Matsuyuki Shirota, Thi Anh Mai Pham, Ayako Matsuzawa, Kei Otsuka, Chikashi Ishioka, Takahiro Mori, Natsuko Chiba

    Cell reports　42　(8)　112850-112850　2023/07/21

    DOI： 10.1016/j.celrep.2023.112850 　

    More details Close

    The BRCA1-interacting protein Obg-like ATPase 1 (OLA1) functions in centriole duplication. In this study, we show the role of the mitotic kinase Aurora A in the reduction of centrosomal OLA1. Aurora A binds to and polyubiquitinates OLA1, targeting it for proteasomal degradation. NIMA-related kinase 2 (NEK2) phosphorylates the T124 residue of OLA1, increases binding of OLA1 to Aurora A and OLA1 polyubiquitination by Aurora A, and reduces centrosomal OLA1 in G2 phase. The kinase activity of Aurora A suppresses OLA1 polyubiquitination. The decrease in centrosomal OLA1 caused by Aurora A-mediated polyubiquitination promotes the recruitment of pericentriolar material proteins in G2 phase. The E3 ligase activity of Aurora A is critical for centrosome amplification induced by its overexpression. The results suggest a dual function of Aurora A as an E3 ubiquitin ligase and a kinase in the regulation of centrosomal OLA1, which is essential for proper centrosome maturation in G2 phase.

  5. 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 　

    More details Close

    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.

  6. 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 　

    More details Close

    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.

  7. 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 　

    More details Close

    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.

  8. 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

  9. 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 　

    More details Close

    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.

  10. Structural basis of the selective sugar transport in sodium-glucose cotransporters. International-journal

    Kazuyo Kamitori, Matsuyuki Shirota, Yuichiro Fujiwara

    Journal of molecular biology　167464-167464　2022/01/22

    DOI： 10.1016/j.jmb.2022.167464 　

    More details Close

    Sodium-glucose cotransporters (SGLTs) are responsible for sugar absorption in small intestine and renal tubule epithelial cells. These proteins have attracted clinical attention as a cause of malabsorption and as a target for diabetes drugs. Each SGLT isoform has strict selectivity for its monosaccharide substrate. Few studies have attempted to elucidate the structural basis of sugar selectivity by allowing generating SGLT mutants that bind substrates not normally transported or by reproducing the substrate specificity of other isoforms. In this study, we built a structural homology model for the substrate binding states of human SGLT1 (hSGLT1), which primarily transports glucose and galactose. We also performed electrophysiological analysis of hSGLT1 using various natural sugars and mutants. By mutating the K321 residue, which forms hydrophilic interactions in the sugar binding pocket, we induced mannose and allose transport. We also changed the glucose/galactose transport ratio, which reproduces the substrate specificity of the prokaryotic galactose transporter. By adding mutations one-by-one to the residues in the binding pocket, we were able to reproduce the substrate specificity of SGLT4, which transports fructose. This suggests that fructose, which exhibits various structures in equilibrium, binds to SGLT in a pyranose conformation. These results reveal one state of the structural basis that determines selective transport by SGLT. These findings will be useful for predicting the substrates of other glucose transporters and to design effective inhibitors.

  11. 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 　

    More details Close

    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.

  12. Current status and future perspectives of the evaluation of missense variants by using three-dimensional structures of proteins.

    Matsuyuki Shirota, Kengo Kinoshita

    Biophysics and physicobiology　19　e190023　2022

    DOI： 10.2142/biophysico.bppb-v19.0023 　

  13. Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator

    Mitsuhiro Yamada, Ikuko N. Motoike, Kaname Kojima, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Fumiki Katsuoka, Shu Tadaka, Matsuyuki Shirota, Miyuki Sakurai, Tomohiro Nakamura, Yohei Hamanaka, Kichiya Suzuki, Junichi Sugawara, Soichi Ogishima, Akira Uruno, Eiichi N. Kodama, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Ayumi Mitsune, Takashi Ohe, Kengo Kinoshita, Masakazu Ichinose, Hisatoshi Sugiura, Masayuki Yamamoto

    Communications Biology　4　(1)　2021/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-021-02813-8 　

    eISSN： 2399-3642

    More details Close

    <title>Abstract</title>Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the <italic>RNF5/AGER</italic> locus including <italic>AGER</italic> rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (<italic>NOS2, SPSB2</italic> and <italic>RIPOR2</italic>) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

  14. 代謝プロファイルに影響を与える遺伝要因の網羅的解析

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 菱沼 英史, 青木 裕一, 田高 周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　94回　[P-837]　2021/11

    Publisher: (公社)日本生化学会

  15. BRCA1/ATF1-mediated transactivation is involved in resistance to PARP inhibitors and cisplatin International-journal Peer-reviewed

    Shino Endo, Yuki Yoshino, Matsuyuki Shirota, Gou Watanabe, Natsuko Chiba

    Cancer Research Communications　1　(2)　90-105　2021/11

    DOI： 10.1158/2767-9764.CRC-21-0064 　

    More details Close

    UNLABELLED: Homologous recombination (HR)-deficient cells are sensitive to PARP inhibitors through a synthetic lethal effect. We previously developed an HR activity assay named Assay of Site-Specific HR Activity (ASHRA). Here, we evaluated the HR activity of 30 missense variants of BRCA1 by ASHRA and found that several BRCA1 variants showed intermediate HR activity, which was not clearly discerned by our previous analyses using a conventional method. HR activity measured by ASHRA was significantly correlated with sensitivity to olaparib. However, cells expressing the severely HR-deficient BRCA1-C61G variant were resistant to olaparib, and resistance was dependent on high expression of activating transcription factor 1 (ATF1), which binds to BRCA1 and activates the transcription of target genes to regulate cell proliferation. The BRCA1-C61G variant bound to ATF1 and stimulated ATF1-mediated transactivation similar to wild-type BRCA1. High expression of ATF1 conferred resistance to olaparib and cisplatin activating BRCA1/ATF1-mediated transcription without affecting HR activity in BRCA2-knockdown or RAD51-knockdown cells, but not in BRCA1-knockdown cells. These results suggest that ASHRA is a useful method to evaluate HR activity in cells and to predict the sensitivity to PARP inhibitors. The expression level of ATF1 might be an important biomarker of the effect of PARP inhibitors and platinum agents on HR-deficient tumors with the BRCA1-C61G variant or alteration of non-BRCA1 HR factors such as BRCA2 and RAD51. SIGNIFICANCE: ASHRA could evaluate HR activity in cells and predict the sensitivity to PARP inhibitors. High expression level of ATF1 may predict the resistance of BRCAness tumors with alterations of non-BRCA1 HR factors to PARP inhibitors and platinum agents.

  16. Wnt5a in cancer-associated fibroblasts promotes colorectal cancer progression. International-journal

    Tomoaki Hirashima, Hideaki Karasawa, Takashi Aizawa, Takashi Suzuki, Akihiro Yamamura, Hideyuki Suzuki, Taiki Kajiwara, Hiroaki Musha, Ryo Funayama, Matsuyuki Shirota, Shinobu Ohnuma, Keiko Nakayama, Michiaki Unno

    Biochemical and biophysical research communications　568　37-42　2021/09/03

    DOI： 10.1016/j.bbrc.2021.06.062 　

    More details Close

    Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and have been shown to promote cancer aggressiveness. In our previous study, analysis of expression profiles obtained from paired CAFs and normal fibroblasts from colorectal cancer (CRC) tissue revealed that gene sets related to the Wnt signaling pathway were highly enriched in colorectal CAFs. Furthermore, among the components of the β-catenin-independent Wnt pathway, Wnt5a was highly expressed in CAFs. Since Wnt5a is considered to be a regulator of CRC progression in CAFs, we performed immunohistochemical analysis on Wnt5a in 171 patients who underwent surgery for CRC. Positive staining for Wnt5a was often found in cancer stroma, particularly in fibromatous areas, although the immunoreactivity for Wnt5a was weak in cancer cells. Wnt5a status in CAFs was significantly associated with tumor size, depth of invasion, lymphatic and vascular invasion, lymph node metastasis, TNM stage, and recurrence. Subsequent in vitro analyses using human recombinant Wnt5a protein revealed that cancer cell proliferation and migration were significantly increased by stimulation with Wnt5a. Our findings suggest that Wnt5a-derived CAFs play a crucial role in CRC progression and have potential as a target of anti-cancer therapies.

  17. Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis in colorectal cancer. International-journal

    Yasushi Mochizuki, Ryo Funayama, Matsuyuki Shirota, Yuna Kikukawa, Masahiro Ohira, Hideaki Karasawa, Minoru Kobayashi, Shinobu Ohnuma, Michiaki Unno, Keiko Nakayama

    International journal of cancer　149　(10)　1787-1800　2021/08/04

    DOI： 10.1002/ijc.33758 　

    More details Close

    The splicing of microexons (very small exons) is frequently dysregulated in the brain of individuals with autism spectrum disorder. However, little is known of the patterns, regulatory mechanisms, and roles of microexon splicing in cancer. We here examined the transcriptome-wide profile of microexon splicing in matched colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between CRC and normal tissue. The 21 genes harboring the differentially spliced microexons were enriched in gene ontology terms related to cell adhesion and migration. RNA interference-mediated knockdown experiments identified two splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC cells. RBFOX2 and PTBP1 were found to directly bind to microexon-containing pre-mRNAs and to control their splicing in such cells. Differential microexon splicing was shown to be due, at least in part, to altered expression of RBFOX2 and PTBP1 in CRC tissue compared with matched normal tissue. Finally, we found that changes in the pattern of microexon splicing were associated with CRC metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1 might influence CRC metastasis through the regulation of microexon splicing.

  18. Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations

    Shio Mitsuzawa, Naoki Suzuki, Tetsuya Akiyama, Mitsuru Ishikawa, Takefumi Sone, Jiro Kawada, Ryo Funayama, Matsuyuki Shirota, Hiroaki Mitsuhashi, Satoru Morimoto, Kensuke Ikeda, Tomomi Shijo, Akiyuki Ohno, Naoko Nakamura, Hiroya Ono, Risako Ono, Shion Osana, Tadashi Nakagawa, Ayumi Nishiyama, Rumiko Izumi, Shohei Kaneda, Yoshiho Ikeuchi, Keiko Nakayama, Teruo Fujii, Hitoshi Warita, Hideyuki Okano, Masashi Aoki

    Stem Cell Reports　16　(6)　1527-1541　2021/06/08

    DOI： 10.1016/j.stemcr.2021.04.021 　

    ISSN： 2213-6711

  19. GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals. International-journal

    Kosuke Shido, Kaname Kojima, Matsuyuki Shirota, Kenshi Yamasaki, Ikuko N Motoike, Atsushi Hozawa, Soichi Ogishima, Naoko Minegishi, Kozo Tanno, Fumiki Katsuoka, Gen Tamiya, Setsuya Aiba, Masayuki Yamamoto, Kengo Kinoshita

    The Journal of investigative dermatology　141　(11)　2749-2752　2021/04/14

    DOI： 10.1016/j.jid.2021.02.762 　

  20. 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 　

    More details Close

    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.

  21. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. International-journal

    Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　49　(D1)　D536-D544　2021/01/08

    DOI： 10.1093/nar/gkaa1034 　

    More details Close

    In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.

  22. Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia.

    Yasuo Uchida, Tomoya Higuchi, Matsuyuki Shirota, Satoshi Kagami, Daisuke Saigusa, Seizo Koshiba, Jun Yasuda, Gen Tamiya, Shinichi Kuriyama, Kengo Kinoshita, Nobuo Yaegashi, Masayuki Yamamoto, Tetsuya Terasaki, Junichi Sugawara

    Biological & pharmaceutical bulletin　44　(6)　804-815　2021

    DOI： 10.1248/bpb.b20-01043 　

    More details Close

    The purpose of the present study was to identify a plasma protein biomarker able to predict pre-eclampsia (PE). Comprehensive quantitative proteomics using mass spectrometry with sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) was applied to plasma samples of 7 PE and 14 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE), and 11 proteins were selected as candidates potentially able to differentiate the two groups. Plasmas collected at gestational weeks 14-24 from 36 PE and 120 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE) were used to conduct selected reaction monitoring quantification analysis, optimize protein combinations and conduct internal validation, which consisted of 30 iterations of 10-fold cross-validation using multivariate logistic regression and receiver operating characteristic (ROC) analysis. The combination of afamin, fibronectin, and sex-hormone-binding globulin was selected as the best candidate. The 3-protein combination predictive model (predictive equation and cut-off value) generated using the internal validation subjects was successfully validated in another group of validation subjects (36 PE and 54 healthy (for PE subjects, plasma samples were taken before onset of PE)) and showed good predictive performance, with the area under the curve (AUC) 0.835 and odds ratio 13.43. In conclusion, we newly identified a 3-protein combination biomarker and established a predictive equation and cut-off value that can predict the onset of PE based on analysis of plasma samples collected during gestational weeks 14-24.

  23. Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population

    Seizo Koshiba, Ikuko N. Motoike, Daisuke Saigusa, Jin Inoue, Yuichi Aoki, Shu Tadaka, Matsuyuki Shirota, Fumiki Katsuoka, Gen Tamiya, Naoko Minegishi, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

    Communications Biology　3　(1)　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-020-01383-5 　

    eISSN： 2399-3642

    More details Close

    <title>Abstract</title> We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.

  24. 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 　

    More details Close

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

  25. Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy International-journal Peer-reviewed

    Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

    Medical Mass Spectrometry　4　(1)　36-49　2020/04/16

    DOI： 10.24508/mms.2020.06.001 　

  26. 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 　

    More details Close

    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.

  27. 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　2020/01/10

    DOI： 10.1053/j.gastro.2020.01.005 　

    More details Close

    BACKGROUND AND 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 sequencing DNA 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 (controls). In replication studies, we sequenced DNA from patients with early-onset CP (20 y or younger), not associated with alcohol consumption, from France (n=470) or 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 13/300 cases (4.3%) and 1/1070 controls (0.1%) from Japan (OR, 48.4; 95% 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 controls (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 cases vs controls (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 cases vs controls (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut given cerulein developed more severe pancreatitis than control mice, demonstrated 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.

  28. 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

    More details Close

    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.

  29. 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 　

    More details Close

    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.

  30. コホート調査における代謝プロファイルの経時変化の解析

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 菱沼 英史, 青木 裕一, 田 高周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　92回　[1T12a-04]　2019/09

    Publisher: (公社)日本生化学会

  31. Cancer-associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer. Peer-reviewed

    Aizawa T, Karasawa H, Funayama R, Shirota M, Suzuki T, Maeda S, Suzuki H, Yamamura A, Naitoh T, Nakayama K, Unno M

    Cancer medicine　2019/08

    DOI： 10.1002/cam4.2523 　

  32. Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. International-journal Peer-reviewed

    Tetsuya Akiyama, Naoki Suzuki, Mitsuru Ishikawa, Koki Fujimori, Takefumi Sone, Jiro Kawada, Ryo Funayama, Fumiyoshi Fujishima, Shio Mitsuzawa, Kensuke Ikeda, Hiroya Ono, Tomomi Shijo, Shion Osana, Matsuyuki Shirota, Tadashi Nakagawa, Yasuo Kitajima, Ayumi Nishiyama, Rumiko Izumi, Satoru Morimoto, Yohei Okada, Takayuki Kamei, Mayumi Nishida, Masahiro Nogami, Shohei Kaneda, Yoshiho Ikeuchi, Hiroaki Mitsuhashi, Keiko Nakayama, Teruo Fujii, Hitoshi Warita, Hideyuki Okano, Masashi Aoki

    EBioMedicine　45　362-378　2019/07

    DOI： 10.1016/j.ebiom.2019.06.013 　

    More details Close

    BACKGROUND: The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. METHOD: Two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs possessing the single amino acid difference (p.H517D) in the fused in sarcoma (FUS) were constructed. By combining MN reporter lentivirus, MN specific phenotype was analyzed. Moreover, RNA profiling of isolated axons were conducted by applying the microfluidic devices that enable axon bundles to be produced for omics analysis. The relationship between the target gene, which was identified as a pathological candidate in ALS with RNA-sequencing, and the MN phenotype was confirmed by intervention with si-RNA or overexpression to hiPSCs-derived MNs and even in vivo. The commonality was further confirmed with other ALS-causative mutant hiPSCs-derived MNs and human pathology. FINDINGS: We identified aberrant increasing of axon branchings in FUS-mutant hiPSCs-derived MN axons compared with isogenic controls as a novel phenotype. We identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. The commonality of those phenotypes was further confirmed with other ALS causative mutation than FUS. INTERPRETATION: Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching. FUND: Japan Agency for Medical Research and development; Japanese Ministry of Education, Culture, Sports, Science and Technology Clinical Research, Innovation and Education Center, Tohoku University Hospital; Japan Intractable Diseases (Nanbyo) Research Foundation; the Kanae Foundation for the Promotion of Medical Science; and "Inochi-no-Iro" ALS research grant.

  33. 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

    More details Close

    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.

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

    Iwasawa S, Yanagi K, Kikuchi A, Kobayashi Y, Haginoya K, Matsumoto H, Kurosawa K, Ochiai M, Sakai Y, Fujita A, Miyake N, Niihori T, Shirota M, Funayama R, Nonoyama S, Ohga S, Kawame H, Nakayama K, Aoki Y, Matsumoto N, Kaname T, Matsubara Y, Shoji W, Kure S

    Annals of neurology　85　(6)　927-933　2019/04

    DOI： 10.1002/ana.25481 　

    ISSN： 0364-5134

    More details Close

    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.

  35. 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

  36. 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. Peer-reviewed

    Tadaka S, Katsuoka F, Ueki M, Kojima K, Makino S, Saito S, Otsuki A, Gocho C, Sakurai-Yageta M, Danjoh I, Motoike IN, Yamaguchi-Kabata Y, Shirota M, Koshiba S, Nagasaki M, Minegishi N, Hozawa A, Kuriyama S, Shimizu A, Yasuda J, Fuse N, Tohoku Medical Megabank Project, Study Group, Tamiya G, Yamamoto M, Kinoshita K

    Human genome variation　6　(1)　28　2019

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41439-019-0059-5 　

    eISSN： 2054-345X

  37. Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2 Peer-reviewed

    Hiroko X. Kondo, Norio Yoshida, Matsuyuki Shirota, Kengo Kinoshita

    The Journal of Physical Chemistry B　2018/12

    Publisher: American Chemical Society ({ACS})

    DOI： 10.1021/acs.jpcb.8b09446 　

  38. Interethnic analyses of blood pressure loci in populations of East Asian and European descent. International-journal Peer-reviewed

    Fumihiko Takeuchi, Masato Akiyama, Nana Matoba, Tomohiro Katsuya, Masahiro Nakatochi, Yasuharu Tabara, Akira Narita, Woei-Yuh Saw, Sanghoon Moon, Cassandra N Spracklen, Jin-Fang Chai, Young-Jin Kim, Liang Zhang, Chaolong Wang, Huaixing Li, Honglan Li, Jer-Yuarn Wu, Rajkumar Dorajoo, Jovia L Nierenberg, Ya Xing Wang, Jing He, Derrick A Bennett, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Hiromi Rakugi, Eitaro Nakashima, Masato Isono, Matsuyuki Shirota, Atsushi Hozawa, Sahoko Ichihara, Tatsuaki Matsubara, Ken Yamamoto, Katsuhiko Kohara, Michiya Igase, Sohee Han, Penny Gordon-Larsen, Wei Huang, Nanette R Lee, Linda S Adair, Mi Yeong Hwang, Juyoung Lee, Miao Li Chee, Charumathi Sabanayagam, Wanting Zhao, Jianjun Liu, Dermot F Reilly, Liang Sun, Shaofeng Huo, Todd L Edwards, Jirong Long, Li-Ching Chang, Chien-Hsiun Chen, Jian-Min Yuan, Woon-Puay Koh, Yechiel Friedlander, Tanika N Kelly, Wen Bin Wei, Liang Xu, Hui Cai, Yong-Bing Xiang, Kuang Lin, Robert Clarke, Robin G Walters, Iona Y Millwood, Liming Li, John C Chambers, Jaspal S Kooner, Paul Elliott, Pim van der Harst, Zhengming Chen, Makoto Sasaki, Xiao-Ou Shu, Jost B Jonas, Jiang He, Chew-Kiat Heng, Yuan-Tsong Chen, Wei Zheng, Xu Lin, Yik-Ying Teo, E-Shyong Tai, Ching-Yu Cheng, Tien Yin Wong, Xueling Sim, Karen L Mohlke, Masayuki Yamamoto, Bong-Jo Kim, Tetsuro Miki, Toru Nabika, Mitsuhiro Yokota, Yoichiro Kamatani, Michiaki Kubo, Norihiro Kato

    Nature communications　9　(1)　5052-5052　2018/11/28

    DOI： 10.1038/s41467-018-07345-0 　

    More details Close

    Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.

  39. Genome analyses for the Tohoku Medical Megabank Project toward establishment of personalized healthcare. Peer-reviewed

    Yasuda J, Kinoshita K, Katsuoka F, Danjoh I, Sakurai-Yageta M, Motoike IN, Kuroki Y, Saito S, Kojima K, Shirota M, Saigusa D, Otsuki A, Kawashima J, Yamaguchi-Kabata Y, Tadaka S, Aoki Y, Mimori T, Kumada K, Inoue J, Makino S, Kuriki M, Fuse N, Koshiba S, Tanabe O, Nagasaki M, Tamiya G, Shimizu R, Takai-Igarashi T, Ogishima S, Hozawa A, Kuriyama S, Sugawara J, Tsuboi A, Kiyomoto H, Ishii T, Tomita H, Minegishi N, Suzuki Y, Suzuki K, Kawame H, Tanaka H, Taki Y, Yaegashi N, Kure S, Nagami F, Tohoku Medical Megabank Project, Study Group, Kosaki K, Sutoh Y, Hachiya T, Shimizu A, Sasaki M, Yamamoto M

    Journal of biochemistry　165　(2)　139-158　2018/11

    DOI： 10.1093/jb/mvy096 　

    ISSN： 0021-924X

    eISSN： 1756-2651

  40. 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

    More details Close

    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.

  41. Biallelic GALM pathogenic variants cause a novel type of galactosemia Peer-reviewed

    Yoichi Wada, AtsuoYoichi 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, co-first authors, corresponding author) Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto

    Genetics in Medicine　21　(6)　1286-1294　2018/10

    DOI： 10.1038/s41436-018-0340-x 　

    ISSN： 1098-3600

    eISSN： 1530-0366

  42. BRCA1-Interacting Protein OLA1 Requires Interaction with BARD1 to Regulate Centrosome Number. International-journal Peer-reviewed

    Yoshino Y, Qi H, Fujita H, Shirota M, Abe S, Komiyama Y, Shindo K, Nakayama M, Matsuzawa A, Kobayashi A, Ogoh H, Watanabe T, Ishioka C, Chiba N

    Molecular cancer research : MCR　16　(10)　1499-1511　2018/10

    DOI： 10.1158/1541-7786.MCR-18-0269 　

    ISSN： 1541-7786

    More details Close

    BRCA1 functions as a tumor suppressor in DNA repair and centrosome regulation. Previously, Obg-like ATPase 1 (OLA1) was shown to interact with BARD1, a heterodimer partner of BRCA1. OLA1 binds to BRCA1, BARD1, and γ-tubulin and functions in centrosome regulation. This study determined that overexpression of wild-type OLA1 (OLA1-WT) caused centrosome amplification due to centriole overduplication in mammary tissue-derived cells. Centrosome amplification induced by overexpression of the cancer-derived OLA1 mutant, which is deficient at regulating centrosome number, occurred in significantly fewer cells than in that induced by overexpression of OLA1-WT. Thus, it was hypothesized that overexpression of OLA1 with normal function efficiently induces centrosome amplification, but not that of OLA1 mutants, which are deficient at regulating centrosome number. We analyzed whether overexpression of OLA1 missense mutants of nine candidate phosphorylation residues, three residues modified with acetylation, and two ATP-binding residues caused centrosome amplification and identified five missense mutants that are deficient in the regulation of centrosome number. Three of them did not bind to BARD1. Two phosphomimetic mutations restored the binding to BARD1 and the efficient centrosome amplification by their overexpression. Knockdown and overexpression of BARD1 also caused centrosome amplification. BARD1 mutant reported in cancer failed to bind to OLA1 and rescue the BARD1 knockdown-induced centrosome amplification and reduced its centrosomal localization. Combined, these data reveal that the OLA1-BARD1 interaction is important for the regulation of centrosome number.Implications: Regulation of centrosome number by BRCA1/BARD1 together with OLA1 is important for the genome integrity to prevent tumor development. Mol Cancer Res; 16(10); 1499-511. ©2018 AACR.

  43. メタボロームGWASによる日本人の代謝プロファイルの解析

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 青木 裕一, 田高 周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　91回　[3T14a-314)]　2018/09

    Publisher: (公社)日本生化学会

  44. Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. International-journal Peer-reviewed

    Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms　23　(6)　406-417　2018/06

    DOI： 10.1111/gtc.12588 　

    ISSN： 1356-9597

    More details Close

    Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.

  45. Bone marrow PDGFRα+Sca-1+-enriched mesenchymal stem cells support survival of and antibody production by plasma cells in vitro through IL-6 Peer-reviewed

    Atsuko Kayaba, Ari Itoh-Nakadai, Kunimichi Niibe, Matsuyuki Shirota, Ryo Funayama, Akiko Sugahara-Tobinai, Yi Li Wong, Masanori Inui, Keiko Nakayama, Toshiyuki Takai

    International Immunology　30　(6)　241-253　2018/05/24

    Publisher: Oxford University Press

    DOI： 10.1093/intimm/dxy018 　

    ISSN： 1460-2377 0953-8178

  46. 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

    More details Close

    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.

  47. 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 　

    More details Close

    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.

  48. ゲノミクスを基盤とした生活習慣病解析最前線 ゲノム情報と連携した日本人多層オミックス参照パネルの意義

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 城田 松之, 青木 裕一, 田高 周, 斎藤 智, 木下 賢吾, 山本 雅之

    糖尿病　61　(Suppl.1)　S-48　2018/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  49. jMorp: Japanese Multi Omics Reference Panel. International-journal Peer-reviewed

    Shu Tadaka, Daisuke Saigusa, Ikuko N Motoike, Jin Inoue, Yuichi Aoki, Matsuyuki Shirota, Seizo Koshiba, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　46　(D1)　D551-D557-D557　2018/01/04

    DOI： 10.1093/nar/gkx978 　

    ISSN： 0305-1048

    More details Close

    We developed jMorp, a new database containing metabolome and proteome data for plasma obtained from >5000 healthy Japanese volunteers from the Tohoku Medical Megabank Cohort Study, which is available at https://jmorp.megabank.tohoku.ac.jp. Metabolome data were measured by proton nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS), while proteome data were obtained by nanoLC-MS. We released the concentration distributions of 37 metabolites identified by NMR, distributions of peak intensities of 257 characterized metabolites by LC-MS, and observed frequencies of 256 abundant proteins. Additionally, correlation networks for the metabolites can be observed using an interactive network viewer. Compared with some existing databases, jMorp has some unique features: (i) Metabolome data were obtained using a single protocol in a single institute, ensuring that measurement biases were significantly minimized; (ii) The database contains large-scale data for healthy volunteers with various health records and genome data and (iii) Correlations between metabolites can be easily observed using the graphical viewer. Metabolites data are becoming important intermediate markers for evaluating the health states of humans, and thus jMorp is an outstanding resource for a wide range of researchers, particularly those in the fields of medical science, applied molecular biology, and biochemistry.

  50. 高精度日本人多層オミックス参照パネルの提供

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 城田 松之, 斎藤 智, 木下 賢吾, 山本 雅之

    生命科学系学会合同年次大会　2017年度　[3P-1369]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  51. Discrepancies between human DNA, mRNA and protein reference sequences and their relation to single nucleotide variants in the human population Peer-reviewed

    Matsuyuki Shirota, Kengo Kinoshita

    DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION　2016　2016/09

    DOI： 10.1093/database/baw124 　

    ISSN： 1758-0463

  52. In silico predicted structural and functional insights of all missense mutations on 2B domain of K1/K10 causing genodermatoses Peer-reviewed

    Santasree Banerjee, Qian Wu, Yuyi Ying, Yanni Li, Matsuyuki Shirota, Dante Neculai, Chen Li

    ONCOTARGET　7　(33)　52766-52780　2016/08

    DOI： 10.18632/oncotarget.10599 　

    ISSN： 1949-2553

  53. The structural origin of metabolic quantitative diversity Peer-reviewed

    Seizo Koshiba, Ikuko Motoike, Kaname Kojima, Takanori Hasegawa, Matsuyuki Shirota, Tomo Saito, Daisuke Saigusa, Inaho Danjoh, Fumiki Katsuoka, Soichi Ogishima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Miyuki Sakurai, Sachiko Hirano, Junichi Nakata, Hozumi Motohashi, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Yoichi Suzuki, Shigeo Kure, Nobuo Yaegashi, Osamu Tanabe, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

    SCIENTIFIC REPORTS　6　31463　2016/08

    DOI： 10.1038/srep31463 　

    ISSN： 2045-2322

  54. Lack of Transcription Triggers H3K27me3 Accumulation in the Gene Body Peer-reviewed

    Masaki Hosogane, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama

    CELL REPORTS　16　(3)　696-706　2016/07

    DOI： 10.1016/j.celrep.2016.06.034 　

    ISSN： 2211-1247

  55. Structural basis for the membrane association of ankyrinG via palmitoylation Peer-reviewed

    Yuichiro Fujiwara, Hiroko X. Kondo, Matsuyuki Shirota, Megumi Kobayashi, Kohei Takeshita, Atsushi Nakagawa, Yasushi Okamura, Kengo Kinoshita

    SCIENTIFIC REPORTS　6　23981　2016/04

    DOI： 10.1038/srep23981 　

    ISSN： 2045-2322

  56. Ion Concentration- and Voltage-Dependent Push and Pull Mechanisms of Potassium Channel Ion Conduction Peer-reviewed

    Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

    PLOS ONE　11　(3)　e0150716　2016/03

    DOI： 10.1371/journal.pone.0150716 　

    ISSN： 1932-6203

  57. Plasma Proteomics Study in the Tohoku Medical Megabank Organization

    Shirota Matsuyuki, Katoh Yasutake, Ikuko Motoike, Kinoshita Kengo, Koshiba Seizo

    Abstracts for Annual Meeting of Japanese Proteomics Society　2016　98-98　2016

    Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)

    DOI： 10.14889/jhupo.2016.0.98.0 　

  58. 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 　

    More details Close

    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.

  59. Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population Peer-reviewed

    Ikuko N. Motoike, Mitsuyo Matsumoto, Inaho Danjoh, Fumiki Katsuoka, Kaname Kojima, Naoki Nariai, Yukuto Sato, Yumi Yamaguchi-Kabata, Shin Ito, Hisaaki Kudo, Ichiko Nishijima, Satoshi Nishikawa, Xiaoqing Pan, Rumiko Saito, Sakae Saito, Tomo Saito, Matsuyuki Shirota, Kaoru Tsuda, Junji Yokozawa, Kazuhiko Igarashi, Naoko Minegishi, Osamu Tanabe, Nobuo Fuse, Masao Nagasaki, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

    BMC GENOMICS　15　673　2014/08

    DOI： 10.1186/1471-2164-15-673 　

    ISSN： 1471-2164

  60. Blind prediction of interfacial water positions in CAPRI Peer-reviewed

    Marc F. Lensink, Iain H. Moal, Paul A. Bates, Panagiotis L. Kastritis, Adrien S. J. Melquiond, Ezgi Karaca, Christophe Schmitz, Marc van Dijk, Alexandre M. J. J. Bonvin, Miriam Eisenstein, Brian Jimenez-Garcia, Solene Grosdidier, Albert Solernou, Laura Perez-Cano, Chiara Pallara, Juan Fernandez-Recio, Jianqing Xu, Pravin Muthu, Krishna Praneeth Kilambi, Jeffrey J. Gray, Sergei Grudinin, Georgy Derevyanko, Julie C. Mitchell, John Wieting, Eiji Kanamori, Yuko Tsuchiya, Yoichi Murakami, Joy Sarmiento, Daron M. Standley, Matsuyuki Shirota, Kengo Kinoshita, Haruki Nakamura, Matthieu Chavent, David W. Ritchie, Hahnbeom Park, Junsu Ko, Hasup Lee, Chaok Seok, Yang Shen, Dima Kozakov, Sandor Vajda, Petras J. Kundrotas, Ilya A. Vakser, Brian G. Pierce, Howook Hwang, Thom Vreven, Zhiping Weng, Idit Buch, Efrat Farkash, Haim J. Wolfson, Martin Zacharias, Sanbo Qin, Huan-Xiang Zhou, Shen-You Huang, Xiaoqin Zou, Justyna A. Wojdyla, Colin Kleanthous, Shoshana J. Wodak

    PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　82　(4)　620-632　2014/04

    DOI： 10.1002/prot.24439 　

    ISSN： 0887-3585

    eISSN： 1097-0134

  61. 2P002 Comprehensive analysis on the conformation and substitution patterns of buried polar residues in protein structures(01A. Protein:Structure,Poster,The 52nd Annual Meeting of the Biophysical Society of Japan(BSJ2014))

    Shirota Matsuyuki, Kinoshita Kengo

    Seibutsu Butsuri　54　(1)　S195　2014

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.54.S195_2 　

  62. 2P072 Analysis of the ion permeation mechanism of Kv1.2 using the molecular dynamics simulations of a single point mutant(01D. Protein: Function,Poster,The 52nd Annual Meeting of the Biophysical Society of Japan(BSJ2014))

    Kondo Hiroko X., Shirota Matsuyuki, Kasahara Kota, Saito Toshiyuki, Kinoshita Kengo

    Seibutsu Butsuri　54　(1)　S206　2014

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.54.S206_6 　

  63. ATTED-II in 2014: Evaluation of Gene Coexpression in Agriculturally Important Plants Peer-reviewed

    Takeshi Obayashi, Yasunobu Okamura, Satoshi Ito, Shu Tadaka, Yuichi Aoki, Matsuyuki Shirota, Kengo Kinoshita

    Plant and Cell Physiology　55　(1)　e6　2014/01

    Publisher: Oxford University Press ({OUP})

    DOI： 10.1093/pcp/pct178 　

    ISSN： 1471-9053

  64. ATTED-II in 2014: Evaluation of Gene Coexpression in Agriculturally Important Plants Peer-reviewed

    Takeshi Obayashi, Yasunobu Okamura, Satoshi Ito, Shu Tadaka, Yuichi Aoki, Matsuyuki Shirota, Kengo Kinoshita

    PLANT AND CELL PHYSIOLOGY　55　(1)　e6　2014/01

    DOI： 10.1093/pcp/pct178 　

    ISSN： 0032-0781

    eISSN： 1471-9053

  65. [Molecular dynamics simulation, ion channel, dynamic structure, bioinformatics]. Peer-reviewed

    Kasahara K, Shirota M, Kino-Shita K

    Seikagaku. The Journal of Japanese Biochemical Society　85　(8)　656-662　2013/08

    ISSN： 0037-1017

  66. Analyses of the general rule on residue pair frequencies in local amino acid sequences of soluble, ordered proteins Peer-reviewed

    Matsuyuki Shirota, Kengo Kinoshita

    PROTEIN SCIENCE　22　(6)　725-733　2013/06

    DOI： 10.1002/pro.2255 　

    ISSN： 0961-8368

  67. Ion Concentration-Dependent Ion Conduction Mechanism of a Voltage-Sensitive Potassium Channel Peer-reviewed

    Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

    PLOS ONE　8　(2)　e56342　2013/02

    DOI： 10.1371/journal.pone.0056342 　

    ISSN： 1932-6203

  68. 2SCA-03 Molecular Dynamics Study on Ion Conduction Mechanisms of a Voltage-sensitive Potassium Channel(2SCA Single Ion Channels updated : From elementary processes to disease treatments,Symposium,The 51th Annual Meeting of the Biophysical Society of Japan)

    Kasahara Kota, Shirota Matsuyuki, Saito Toshiyuki, Kondo Hiroko, Kinoshita Kengo

    Seibutsu Butsuri　53　(1)　S93　2013

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.53.S93_6 　

  69. 1P106 Evaluating the impact of charged residues in proton channel Hv1 by computer simulations(03.Membrane proteins,Poster,The 51st Annual Meeting of the Biophysical Society of Japan)

    Shirota Matsuyuki, Chiba Susumu, Kasahara Kota, Kondo Hiroko, Kinoshita Kengo

    Seibutsu Butsuri　53　(1)　S123　2013

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.53.S123_4 　

  70. 1P107 Behavior of potassium ions around the potassium channel in relation to permeation events(03.Membrane proteins,Poster,The 51st Annual Meeting of the Biophysical Society of Japan)

    Saito Toshiyuki, Kasahara Kota, Shirota Matsuyuki, Kondo Hiroko, Kinoshita Kengo

    Seibutsu Butsuri　53　(1)　S123　2013

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.53.S123_5 　

  71. Comprehensive Classification and Diversity Assessment of Atomic Contacts in Protein-Small Ligand Interactions Peer-reviewed

    Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

    JOURNAL OF CHEMICAL INFORMATION AND MODELING　53　(1)　241-248　2013/01

    DOI： 10.1021/ci300377f 　

    ISSN： 1549-9596

  72. 3PT131 Homology modeling and molecular dynamics study of proton permeation pathway in a channel protein(The 50th Annual Meeting of the Biophysical Society of Japan)

    Chiba Susumu, Kasahara Kota, Shirota Matsuyuki, Kinoshita Kengo

    Seibutsu Butsuri　52　S163　2012

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.52.S163_2 　

  73. 3E1046 Optimization of protein model structures according to statistical potentials with different reference states(Proteins:Structure,Oral Presentation)

    Shirota Matsuyuki, Kinoshita Kengo

    Seibutsu Butsuri　52　S65　2012

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.52.S65_2 　

  74. Prediction of protein-protein complex structures Peer-reviewed

    Eiji Kanamori, Yoichi Murakami, Joy Sarmiento, Shide Uang, Daron M. Standley, Matsuyuki Shirota, Kengo Kinoshita, Yuko Tsucillya, Junicill Higo, Haruki Nakamura

    Biomolecular Forms and Functions: A Celebration of 50 Years of the Ramachandran Map　160-172　2012/01/01

    Publisher: World Scientific Publishing Co.

    DOI： 10.1142/9789814449144_0013 　

  75. Absolute quality evaluation of protein model structures using statistical potentials with respect to the native and reference states Peer-reviewed

    Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

    PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　79　(5)　1550-1563　2011/05

    DOI： 10.1002/prot.22982 　

    ISSN： 0887-3585

    eISSN： 1097-0134

  76. 3G0948 An absolute quality evaluation method of protein model structures developed based only on the native structure data set(3G Protein: Structure 3,The 49th Annual Meeting of the Biophysical Society of Japan)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    Seibutsu Butsuri　51　S129　2011

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.51.S129_2 　

  77. SAHG, a comprehensive database of predicted structures of all human proteins Peer-reviewed

    Chie Motono, Junichi Nakata, Ryotaro Koike, Kana Shimizu, Matsuyuki Shirota, Takayuki Amemiya, Kentaro Tomii, Nozomi Nagano, Naofumi Sakaya, Kiyotaka Misoo, Miwa Sato, Akinori Kidera, Hidekazu Hiroaki, Tsuyoshi Shirai, Kengo Kinoshita, Tamotsu Noguchi, Motonori Ota

    NUCLEIC ACIDS RESEARCH　39　(Database issue)　D487-D493　2011/01

    DOI： 10.1093/nar/gkq1057 　

    ISSN： 0305-1048

  78. 3P026 Estimation of native-like state of protein structure using statistical potentials for protein structure prediction(Protein: Structure,The 48th Annual Meeting of the Biophysical Society of Japan)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    Seibutsu Butsuri　50　(2)　S149　2010

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.50.S149_4 　

  79. Development of a new meta-score for protein structure prediction from seven all-atom distance dependent potentials using support vector regression. Peer-reviewed

    Shirota, Matsuyuki Ishida, Takashi Kinoshita, Kengo

    Genome Inform　23　(1)　149-158　2009/10

    Publisher: 1

    ISSN： 0919-9454

  80. Analyses on hydrophobicity and attractiveness of all-atom distance-dependent potentials Peer-reviewed

    Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

    PROTEIN SCIENCE　18　(9)　1906-1915　2009/09

    DOI： 10.1002/pro.201 　

    ISSN： 0961-8368

  81. 1P-018 Development of a meta-score for protein structure prediction(Protein:Structure, The 47th Annual Meeting of the Biophysical Society of Japan)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    Seibutsu Butsuri　49　S66　2009

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.49.S66_3 　

  82. Effects of surface-to-volume ratio of proteins on hydrophilic residues: Decrease in occurrence and increase in buried fraction Peer-reviewed

    Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

    PROTEIN SCIENCE　17　(9)　1596-1602　2008/09

    DOI： 10.1110/ps.035592.108 　

    ISSN： 0961-8368

  83. 1P-012 Effect of protein size on statistical potentials(The 46th Annual Meeting of the Biophysical Society of Japan)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    Seibutsu Butsuri　48　S22　2008

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.48.S22_5 　

  84. 1P005 Effect of domain size on residue frequency and propensity to be buried(Proteins-structure and structure-function relationship,Oral Presentations)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    Seibutsu Butsuri　47　S24　2007

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.47.S24_4 　

  85. 2P060 Structural diversity of AMP binding sites in proteins(Proteins-structure and structure-function relationship,Poster Presentations)

    Okamoto Megumi, Tsuchiya Yuko, Shirota Matsuyuki, Kinoshita Kengo

    Seibutsu Butsuri　47　S128　2007

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.47.S128_1 　

  86. Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions Peer-reviewed

    Y Suzuki, R Yamashita, M Shirota, Y Sakakibara, J Chiba, J Mizushima-Sugano, K Nakai, S Sugano

    GENOME RESEARCH　14　(9)　1711-1718　2004/09

    DOI： 10.1101/gr.2435604 　

    ISSN： 1088-9051

  87. Large-scale collection and characterization of promoters of human and mouse genes Peer-reviewed

    Yutaka Suzuki, Riu Yamashita, Matsuyuki Shirota, Yuta Sakakibara, Joe Chiba, Junko Mizushima-Sugano, Alexander E. Kel, Takahiro Arakawa, Piero Carninci, Jun Kawai, Yoshihide Hayashizaki, Toshihisa Takagi, Kenta Nakai, Sumio Sugano

    In Silico Biology　4　(4)　429-444　2004

    Publisher: 4

    ISSN： 1386-6338

Show all ︎Show first 5

Misc. 31

  1. 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

  2. 代謝プロファイルに影響を与える遺伝要因の網羅的解析

    小柴生造, 小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 井上仁, 菱沼英史, 青木裕一, 青木裕一, 田高周, 田高周, 城田松之, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

    日本生化学会大会(Web)　94th　2021

  3. 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

  4. 次世代型プロテオミクスによる妊娠高血圧腎症の診断マーカーの同定

    樋口友也, 内田康雄, 内田康雄, 加賀美智史, 城田松之, 城田松之, 三枝大輔, 三枝大輔, 小柴生造, 小柴生造, 栗山進一, 栗山進一, 菅原準一, 菅原準一, 寺崎哲也, 寺崎哲也

    日本薬学会東北支部大会講演要旨集　58th　2019

  5. Structural Basis for the Membrane Association of Ankyrin

    藤原祐一郎, 近藤寛子, 城田松之, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾

    生物物理(Web)　58　(3)　2018

    ISSN： 1347-4219

  6. 電位依存性カリウムチャネル変異体の電位依存的な不活性化機構の解析

    近藤寛子, 城田松之, 城田松之, 城田松之, 鷹野優, 木下賢吾, 木下賢吾, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　18th　2018

  7. ゲノム情報と連携した日本人多層オミックス参照パネルの意義

    小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 城田松之, 城田松之, 青木裕一, 青木裕一, 田高周, 田高周, 斎藤智, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之

    糖尿病(Web)　61　(Suppl)　2018

    ISSN： 1881-588X

  8. 3次元Lattice構造の比較分類

    加賀谷祐輝, 城田松之, 城田松之, 木下賢吾, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　17th　2017

  9. 低頻度一塩基多型のタンパク質立体構造を利用した機能アノテーションに向けて

    城田松之, 木下賢吾, 木下賢吾, 木下賢吾

    日本生化学会大会(Web)　90th　2017

  10. A study of dynamics of palmitoylated Ankyrin-G around a lipid bilayer by coarse-grained simulations Peer-reviewed

    Kondo XH, Fujiwara Y, Shirota M, Kinoshita K

    Journal of Physiological Sciences　67　(Supplement1)　S43　2017

  11. 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

  12. マルチオミクスが解き明かす疾患生物学 日本人多層オミックス参照パネルの拡張

    小柴 生造, 三枝 大輔, 元池 育子, 小島 要, 城田 松之, 齋藤 智, 勝岡 史城, 河合 洋介, 山口 由美, 田邉 修, 長崎 正郎, 安田 純, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　89回　[1S05-5]　2016/09

    Publisher: (公社)日本生化学会

  13. 日本人多層オミックス参照パネルの公開

    小柴生造, 加藤恭丈, 三枝大輔, 元池育子, 城田松之, 斎藤智, 田邉修, 安田純, 木下賢吾, 山本雅之

    日本生化学会大会(Web)　88th　4T21L-07(3P0816) (WEB ONLY)-07(3P0816)]　2015/12

    Publisher: (公社)日本生化学会

  14. 電位依存性プロトンチャネルVSOPにおける亜鉛イオンの役割についての計算機シミュレーション

    近藤寛子, 城田松之, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　15th　2015

  15. Plasma proteome analysis for a large-scale population-based cohort study

    Katoh Yasutake, Koshiba Seizo, Igarashi Kazuhiko, Yamamoto Masayuki, Tanabe Osamu, Ebina Masayuki, Shirota Matsuyuki, Motoike Ikuko, Kinoshita Kengo, Kudo Hisaaki, Nobukuni Takahiro, Minegishi Naoko, Saigusa Daisuke

    Abstracts for Annual Meeting of Japanese Proteomics Society　2015　(0)　62-62　2015

    Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)

    DOI： 10.14889/jhupo.2015.0.62.0 　

  16. Effect of protein structure and genome sequence in variant analysis

    Matsuyuki Shirota, Kengo Kinoshita

    GENES & GENETIC SYSTEMS　89　(6)　292-292　2014/12

    ISSN： 1341-7568

    eISSN： 1880-5779

  17. 大規模住民コホート研究のためのLC‐MS/MS血漿プロテオーム解析の標準化

    加藤恭丈, 蝦名真行, 城田松之, 木下賢吾, 五十嵐和彦, 田邉修, 山本雅之

    日本生化学会大会(Web)　87th　3P-505 (WEB ONLY)-505]　2014/10

    Publisher: (公社)日本生化学会

  18. LC/MSによる分離技術を基盤とした高感度メタボローム解析手法の開発と臨床応用に関する研究

    三枝大輔, 城田松之, 小柴正造, 菅原準一, 田邉修, 本橋ほづみ, 山本雅之

    BMSコンファレンス講演要旨集　41st　122-126　2014/07/07

  19. タンパク質機能解析に向けた立体構造情報の活用基盤の構築

    木下賢吾, 木下賢吾, 木下賢吾, 村上洋一, 城田松之, 城田松之

    日本農芸化学会大会講演要旨集(Web)　2014　2014

    ISSN： 2186-7976

  20. The standardization of parameters for plasma proteome samples in a large clinical cohort

    Katoh Yasutake, Ebina Masayuki, Shirota Matsuyuki, Kinoshita Kengo, Igarashi Kazuhiko, Tanabe Osamu

    Abstracts for Annual Meeting of Japanese Proteomics Society　2014　(0)　111-111　2014

    Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)

    DOI： 10.14889/jhupo.2014.0.111.0 　

  21. タンパク質構造機能相関再考 分子動力学シミュレーションによるタンパク質動的構造の解明:電位依存カリウムチャネルでの適用を例として

    笠原浩太, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾

    生化学　85　(8)　2013

    ISSN： 0037-1017

  22. Exploring the proton permeation pathway by using homology modeling and molecular dynamics simulation of the Hv1 proton channel

    Matsuyuki Shirota, Susumu Chiba, Kota Kasahara, Kengo Kinoshita

    JOURNAL OF PHYSIOLOGICAL SCIENCES　63　S55-S55　2013

    ISSN： 1880-6546

  23. Prediction of Protein-Protein Complex Structures Using a Docking Server, surFit

    Eiji Kanamori, Yuko Tsuchiya, Yoichi Murakami, Joy Sarmiento, Shide Liang, Daron Standley, Matsuyuki Shirota, Kengo Kinoshita, Haruki Nakamura

    PROTEIN SCIENCE　21　178-178　2012/08

    ISSN： 0961-8368

  24. Analysis of the Constraints on Amino Acid Pairs in Proteins

    Matsuyuki Shirota, Kengo Kinoshita

    IPSJ SIG technical reports　2012　(18)　1-2　2012/03/21

    Publisher: Information Processing Society of Japan (IPSJ)

    ISSN： 0919-6072

    More details Close

    Various constraints are imposed on amino acid sequences of native proteins in order to maintain their structures and functions. To clarify these constraints, we analyzed the propensities of amino acid pairs at particular sequence separations. As results, we found that identical amino acid pairs in local amino acid sequence occur more frequently than random in intrinsically disordered proteins, and that the occurrence of amino acid pairs are strongly dependent on the order of the two amino acids.

  25. タンパク質におけるアミノ酸組成の偏りとアミノ酸配列の一様さ

    城田松之, 木下賢吾, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　12th　2012

  26. K+チャネルにおける溶液イオン濃度依存なイオン透過機構スイッチングに関する分子動力学的解析

    笠原浩太, 城田松之, 木下賢吾, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　12th　2012

  27. VSOPのNa+チャネルを用いたモデリングと分子シミュレーション

    千葉奏, 城田松之, 笠原浩太, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　12th　2012

  28. Analysis of the Constraints on Amino Acid Pairs in Proteins

    城田松之, 木下賢吾, 木下賢吾

    情報処理学会研究報告(CD-ROM)　2011　(6)　2012

    ISSN： 2186-2583

  29. K+チャネルにおける溶液イオン濃度依存なイオン透過機構スイッチングに関する分子動力学的解析

    笠原浩太, 城田松之, 木下賢吾, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　12th　2012

  30. 蛋白質立体構造における4体間相互作用の解析

    城田松之, 木下賢吾, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　11th　2011

  31. ヒトゲノム構造・機能アノテーションデータベースSAHG(Structural Atlas of Human Genome)の構築

    本野千恵, 中田淳一, 清水佳奈, 富井健太郎, 長野希美, 野口保, 廣明秀一, 雨宮崇之, 城田松之, 小池亮太郎, 白井剛, 木下賢吾, 太田元規

    日本蛋白質科学会年会プログラム・要旨集　10th　2010

Show all ︎Show first 5

Research Projects 13

  1. Protein Structure Prediction Competitive

    2006/04 - Present

  2. Prediction and validation of regulatory variants based on DNA/RNA-protein complex structures

    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

  3. 中心体異常とDNA損傷によるゲノム不安定性を標的とする新しいがん治療法の開発

    千葉 奈津子, 吉野 優樹, 渡部 剛, 城田 松之

    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

    2022/04/01 - 2025/03/31

  4. Development of Targeting therapy for centrosome dysregulation in cancer

    Chiba Natsuko

    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

    2019/04/01 - 2022/03/31

    More details Close

    Centrosomes are the major microtubule nucleation centers in animal cells and are critical for forming a bipolar mitotic spindle. Defects in the mechanisms regulating centrosome number are associated with carcinogenesis and cancer progression. Pathogenic variants of BRCA1 cause hereditary breast and ovarian cancer syndrome. We found that BRCA1 regulates the centrosome localization and the activities of the mitotic kinases, Aurora A and PLK1, and plays important roles in centrosome duplication and the centrosomes amplification induced by DNA damage with the BRCA1-binding proteins, BARD1, OLA1, and RACK1. We also showed that cancer-derived mutations and abnormal expression levels of these proteins cause abnormal centrosome duplication and centrosome amplification.

  5. Multi-layer informatics analysis on brain and personality focused on microexons

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Tohoku University

    2019/04/01 - 2021/03/31

  6. Development of information system for functional annotation of genomic sequence alterations by using protein 3D structures

    Shirota Matsuyuki

    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

    2018/04/01 - 2021/03/31

    More details Close

    In this study, we developed an annotation system of nonsynonymous variants in the human genome to select those variants that can affect protein structure and function by evaluating various atomic interactions including hydrophobic interactions, protein-protein interactions, disulfide bonds, hydrogen bonds, and interactions with DNA, RNA, ions and other small ligands in the three-dimensional protein structures in Protein Data Bank. We applied this annotation system to known single nucleotide variants to facilitate interpretation of their functional roles and provided a web system that can annotate the variants of user's interest.

  7. Elucidation of the signaling pathways that induce gene amplification

    NAKAYAMA Keiko

    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 - 2020/03/31

    More details Close

    When the time course of amplification after TGF-β stimulation was examined, cell proliferation had already stopped on the second day after the start of stimulation, but no gene amplification was observed, and amplification occurred on the 28th day. To confirm that this is a universal phenomenon in NMuMG cells, we purchased new NMuMG cells and further cloned the cells by limitting dilution. After stimulation with TGF-β, all the clones stopped growing and then started growing again, avoiding the inhibition of growth by TGF-β, as previously reported. However, no amplification of myc was observed in these clones, suggesting that this is not a universal phenomenon in NMuMG cells.

  8. Elucidation of the mechanism of transcription elongation rate control by histone code

    NAKAYAMA Keiko

    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

    More details Close

    To measure the rate of transcription elongation, we used DRB treatment, an RNA polymerase inhibitor, and BrU labeling of the newly synthesized RNAs to recover the newly synthesized RNAs. We measured the elongation rate of model genes, such as the highly transcribed GAPDH gene. To determine how H3K27me3 modification affects the elongation rate of RNA polymerase in cells, cells were knocked down with SUZ12 and reduced H3K27me3 modification, resulting that H3K27me3 modification is negatively correlated with the elongation rate of transcription. Now, to investigate the comprehensiveness of this phenomenon, we performed RNA seq of a newly synthesized RNA and ChIP seq of H3K27me3.

  9. Elucidation of regulatory mechanism to maintain genome stability by novel BRCA1-interacting molecules and development of cancer therapy

    CHIBA Natsuko

    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

    2016/04/01 - 2019/03/31

    More details Close

    BRCA1 is a tumor suppressor that is associated with hereditary breast and ovarian cancer. BRCA1 functions in DNA repair together with BARD1, a heterodimer partner of BRCA1. We identified BRCA1-interacting proteins, OLA1 and RACK1 and analyzed their function. OLA1 and RACK1 directly bound to BRCA1, and BARD1, localized the centrosomes, and functioned in the regulation of the centrosome duplication. RACK1 was involved in centrosomal localization of BRCA1. Abnormal level of the expression of OLA1 or RACK1 caused dysregulation of centrosome duplication. Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 abolished their interaction and function in centrosome duplication. These results elucidated the novel regulatory mechanism by BRCA1 to maintain genome stability.

  10. Refinement of protein structure prediction by using simulation and database analyses

    Shirota Matsuyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

    More details Close

    Improving the quality of protein models generated by protein structure prediction is a challenging task that can extend the applicability of the predicted models to function prediction and drug design. In this study, known protein structures are utilized for refinement of protein structure models by comprehensively processing all the available structures. The information from known structures are aligned to the human protein sequences by sequence alignment for improving the structure models of human proteins. As applications of the model refinement methods, two genomic analyses were performed. First, amino acid insertions of human protein structures by splicing-in microexons were analyzed by using public RNA-seq data. Second, amino acid variations within the transmembrane domains of G-protein coupled receptors were summarized. The results of these analyses provide g resource for appying model refinement methods.

  11. Verification of genomic diversity required for tumorigenesis

    NAKAYAMA Keiko

    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 - 2017/03/31

    More details Close

    CRISPR/Cas9 library was introduced to NIH3T3 cells and MDA-MD-468 cells to generate cell library which are gene disrupted. Groups of cells which was disrupted a gene by CRISPR/Cas9 system were obtained. These cells were inoculated subcutaneously on the back of immunodeficient mice to grow tumors. Even NIH3T3 cells which were introduced library failed to stable tumorigenesis as well as wild type cells. These data suggested that NIH3T3 population containing different kinds of a single gene disrupted cells did not achieve capability of tumorigenesis. With MDA-MD-462 cells, we observed cells introduced CRISPR/Cas9 library gain function of tumorigenesis compared to wild-type cells.

  12. Genome wide analysis of epigenetic regulation of enhancer activity via H3K27 modifications

    HOSOGANE Masaki, NAKAYAMA Keiko, FUNAYAMA Ryo, SHIROTA Matuyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2015/04/01 - 2017/03/31

    More details Close

    It is still unknown whether H3K27me3 histone modification has a repressive role toward enhancer activity. To address this issue, we performed series of genome wide analysis to map and quantify H3K27me3, H3K27ac, p300 and mRNA expression in H3K27me3-depleted K562 human leukemia cells. We observed that the decrease in H3K27me3 level in enhancer region led to massive accumulation of H3K27ac and p300 at the same enhancer region, whereas the decrease in H3K27me3 in gene body was associated with upregulation of transcription of the same gene. Our results thus provide insights into the causal relationship between H3K27 histone modifications in regulatory elements and gene expression.

  13. Development of a database of buried polar residues in protein structures

    Shirota Matsuyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

    More details Close

    Although hydrophobic interactions are the driving force of protein folding, polar interactions, such as hydrogen bonds, which buried polar residues make are also important for protein structure and function. However, polar residues that are buried in the protein interior and sequestered from water are considered to be exceptional conformations, whose occurrences, intra-molecular interactions and conservations in natural proteins have not been well studied. In this study, I performed a comprehensive survey of the buried polar residues in the non-redundant protein structures of Protein Data Bank (PDB), focusing on patterns of their side-chain interactions and evolutionary conservation. These results highlight the structural and evolutionary importance of buried polar residues in protein structures and will be beneficial for protein structure prediction and protein design.

Show all Show first 5