研究者詳細

顔写真

シロタ　マツユキ
城田　松之
Matsuyuki Shirota
所属
大学院医学系研究科　創生応用医学研究センター　ＡＩフロンティア新医療創生分野
職名
講師
学位

  • 博士（生命科学）（東京大学）

所属学協会 2

  • 日本蛋白質科学会

  • 日本生物物理学会

研究分野 1

  • ライフサイエンス / 形態、構造 / 生物情報学

論文 87

  1. Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population. 国際誌 査読有り

    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年

    DOI： 10.3389/fnins.2024.1437668 　

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    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. 国際誌

    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年12月29日

    DOI： 10.1002/acn3.51977 　

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

  3. jMorp: Japanese Multi-Omics Reference Panel update report 2023. 国際誌 査読有り

    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年11月1日

    DOI： 10.1093/nar/gkad978 　

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    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. 国際誌

    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年7月21日

    DOI： 10.1016/j.celrep.2023.112850 　

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    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. 国際誌

    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年7月11日

    DOI： 10.1016/j.braindev.2023.06.009 　

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

  6. A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor. 国際誌

    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年9月27日

    DOI： 10.1038/s10038-022-01082-5 　

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

  7. Novel POLE mutations identified in patients with IMAGE-I syndrome cause aberrant subcellular localisation and protein degradation in the nucleus. 国際誌

    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年5月9日

    DOI： 10.1136/jmedgenet-2021-108300 　

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

  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年2月

    出版者・発行元： (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. 国際誌

    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年1月28日

    DOI： 10.1038/s10038-022-01017-0 　

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

  10. Structural basis of the selective sugar transport in sodium-glucose cotransporters. 国際誌

    Kazuyo Kamitori, Matsuyuki Shirota, Yuichiro Fujiwara

    Journal of molecular biology　167464-167464　2022年1月22日

    DOI： 10.1016/j.jmb.2022.167464 　

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    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. 国際誌

    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年1月12日

    DOI： 10.1182/bloodadvances.2020003812 　

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

  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年

    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年12月

    出版者・発行元： Springer Science and Business Media LLC

    DOI： 10.1038/s42003-021-02813-8 　

    eISSN：2399-3642

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    <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年11月

    出版者・発行元： (公社)日本生化学会

  15. BRCA1/ATF1-mediated transactivation is involved in resistance to PARP inhibitors and cisplatin 国際誌 査読有り

    Endo S, Yoshino Y, Shirota M, WatanabeG, Chiba N

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

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

  16. Wnt5a in cancer-associated fibroblasts promotes colorectal cancer progression. 国際誌

    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年9月3日

    DOI： 10.1016/j.bbrc.2021.06.062 　

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    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. 国際誌

    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年8月4日

    DOI： 10.1002/ijc.33758 　

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    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年6月8日

    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. 国際誌

    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年4月14日

    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. 国際誌

    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年3月20日

    DOI： 10.1038/s10038-021-00916-y 　

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

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

    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年1月8日

    DOI： 10.1093/nar/gkaa1034 　

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    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年

    DOI： 10.1248/bpb.b20-01043 　

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    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年12月

    出版者・発行元： Springer Science and Business Media LLC

    DOI： 10.1038/s42003-020-01383-5 　

    eISSN：2399-3642

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    <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. 国際誌

    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年7月

    DOI： 10.1038/s41436-020-0836-z 　

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

  25. Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy 国際誌 査読有り

    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年4月16日

    DOI： 10.24508/mms.2020.06.001 　

  26. Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. 国際誌 査読有り

    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年2月26日

    DOI： 10.1371/journal.pgen.1008628 　

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

  27. Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-onset Chronic Pancreatitis. 国際誌 査読有り

    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年1月10日

    DOI： 10.1053/j.gastro.2020.01.005 　

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    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. 国際誌 査読有り

    Niitsuma S, Kudo H, Kikuchi A, Hayashi T, Kumakura S, Kobayashi S, Okuyama Y, Kumagai N, Niihori T, Aoki Y, So T, Funayama R, Nakayama K, Shirota M, Kondo S, Kagami S, Tsukaguchi H, Iijima K, Kure S, Ishii N

    International immunology　2019年12月24日

    DOI： 10.1093/intimm/dxz081 　

    ISSN：0953-8178

  29. Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis. 国際誌 査読有り

    Ozeki M, Aoki Y, Nozawa A, Yasue S, Endo S, Hori Y, Matsuoka K, Niihori T, Funayama R, Shirota M, Nakayama K, Fukao T

    Orphanet journal of rare diseases　14　(1)　215-215　2019年9月11日

    DOI： 10.1186/s13023-019-1191-5 　

  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年9月

    出版者・発行元： (公社)日本生化学会

  31. Cancer-associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer. 査読有り

    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年8月

    DOI： 10.1002/cam4.2523 　

  32. Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. 国際誌 査読有り

    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年7月

    DOI： 10.1016/j.ebiom.2019.06.013 　

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    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. 国際誌 査読有り

    Niihori T, Nagai K, Fujita A, Ohashi H, Okamoto N, Okada S, Harada A, Kihara H, Arbogast T, Funayama R, Shirota M, Nakayama K, Abe T, Inoue SI, Tsai IC, Matsumoto N, Davis EE, Katsanis N, Aoki Y

    American journal of human genetics　104　(6)　1233-1240　2019年6月6日

    DOI： 10.1016/j.ajhg.2019.04.014 　

    ISSN：0002-9297

  34. Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. 国際誌 査読有り

    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年4月

    DOI： 10.1002/ana.25481 　

    ISSN：0364-5134

  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年2月

    出版者・発行元： (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. 査読有り

    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年

    出版者・発行元：

    DOI： 10.1038/s41439-019-0059-5 　

    eISSN：2054-345X

  37. Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2 査読有り

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

    The Journal of Physical Chemistry B　2018年12月

    出版者・発行元： 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. 国際誌 査読有り

    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年11月28日

    DOI： 10.1038/s41467-018-07345-0 　

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    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. 査読有り

    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年11月

    DOI： 10.1093/jb/mvy096 　

    ISSN：0021-924X

    eISSN：1756-2651

  40. Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome. 国際誌 査読有り

    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年11月

    DOI： 10.1016/j.braindev.2018.06.010 　

    ISSN：0387-7604

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

  41. Biallelic GALM pathogenic variants cause a novel type of galactosemia 査読有り

    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, co-first authors, corresponding author

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

    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. 国際誌 査読有り

    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年10月

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

    ISSN：1541-7786

  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年9月

    出版者・発行元： (公社)日本生化学会

  44. Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. 国際誌 査読有り

    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年6月

    DOI： 10.1111/gtc.12588 　

    ISSN：1356-9597

    詳細を見る 詳細を閉じる

    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. 査読有り

    Kayaba A, Itoh-Nakadai A, Niibe K, Shirota M, Funayama R, Sugahara-Tobinai A, Wong YL, Inui M, Nakayama K, Takai T

    International immunology　30　(6)　241-253　2018年5月24日

    出版者・発行元：

    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. 国際誌 査読有り

    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年5月

    DOI： 10.1016/j.braindev.2017.12.015 　

    ISSN：0387-7604

    詳細を見る 詳細を閉じる

    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. 国際誌 査読有り

    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年5月

    DOI： 10.1002/acn3.551 　

    詳細を見る 詳細を閉じる

    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年4月

    出版者・発行元： (一社)日本糖尿病学会

    ISSN：0021-437X

    eISSN：1881-588X

  49. jMorp: Japanese Multi Omics Reference Panel. 国際誌 査読有り

    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年1月4日

    DOI： 10.1093/nar/gkx978 　

    ISSN：0305-1048

    詳細を見る 詳細を閉じる

    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年12月

    出版者・発行元： 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 査読有り

    Matsuyuki Shirota, Kengo Kinoshita

    DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION　2016　2016年9月

    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 査読有り

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

    ONCOTARGET　7　(33)　52766-52780　2016年8月

    DOI： 10.18632/oncotarget.10599 　

    ISSN：1949-2553

  53. The structural origin of metabolic quantitative diversity 査読有り

    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年8月

    DOI： 10.1038/srep31463 　

    ISSN：2045-2322

  54. Lack of Transcription Triggers H3K27me3 Accumulation in the Gene Body 査読有り

    Masaki Hosogane, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama

    CELL REPORTS　16　(3)　696-706　2016年7月

    DOI： 10.1016/j.celrep.2016.06.034 　

    ISSN：2211-1247

  55. Structural basis for the membrane association of ankyrinG via palmitoylation 査読有り

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

    SCIENTIFIC REPORTS　6　23981　2016年4月

    DOI： 10.1038/srep23981 　

    ISSN：2045-2322

  56. Ion Concentration- and Voltage-Dependent Push and Pull Mechanisms of Potassium Channel Ion Conduction 査読有り

    Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

    PLOS ONE　11　(3)　e0150716　2016年3月

    DOI： 10.1371/journal.pone.0150716 　

    ISSN：1932-6203

  57. 東北メディカル・メガバンク機構における血漿プロテオミクス解析

    城田 松之, 加藤 恭丈, 元池 育子, 木下 賢吾, 小柴 生造

    日本プロテオーム学会大会要旨集　2016　98-98　2016年

    出版者・発行元： 日本プロテオーム学会（日本ヒトプロテオーム機構）

    DOI： 10.14889/jhupo.2016.0.98.0 　

  58. Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation. 国際誌 査読有り

    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年10月

    DOI： 10.1212/NXG.0000000000000023 　

    詳細を見る 詳細を閉じる

    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 査読有り

    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年8月

    DOI： 10.1186/1471-2164-15-673 　

    ISSN：1471-2164

  60. Blind prediction of interfacial water positions in CAPRI 査読有り

    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年4月

    DOI： 10.1002/prot.24439 　

    ISSN：0887-3585

    eISSN：1097-0134

  61. 2P002 タンパク質における埋もれた極性残基の構造と置換パターンの網羅的解析(01A. 蛋白質:構造,ポスター,第52回日本生物物理学会年会(2014年度))

    Shirota Matsuyuki, Kinoshita Kengo

    生物物理　54　(1)　S195　2014年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.54.S195_2 　

  62. 2P072 変異体を用いた分子動力学シミュレーションによる電位依存性カリウムチャネルのイオン透過機構の解析(01D. 蛋白質:機能,ポスター,第52回日本生物物理学会年会(2014年度))

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

    生物物理　54　(1)　S206　2014年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.54.S206_6 　

  63. ATTED-II in 2014: Evaluation of Gene Coexpression in Agriculturally Important Plants 査読有り

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

    Plant and Cell Physiology　55　(1)　e6　2014年1月

    出版者・発行元： 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 査読有り

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

    PLANT AND CELL PHYSIOLOGY　55　(1)　e6　2014年1月

    DOI： 10.1093/pcp/pct178 　

    ISSN：0032-0781

    eISSN：1471-9053

  65. [Molecular dynamics simulation, ion channel, dynamic structure, bioinformatics]. 査読有り

    Kasahara K, Shirota M, Kino-Shita K

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

    ISSN：0037-1017

  66. Analyses of the general rule on residue pair frequencies in local amino acid sequences of soluble, ordered proteins 査読有り

    Matsuyuki Shirota, Kengo Kinoshita

    PROTEIN SCIENCE　22　(6)　725-733　2013年6月

    DOI： 10.1002/pro.2255 　

    ISSN：0961-8368

  67. Ion Concentration-Dependent Ion Conduction Mechanism of a Voltage-Sensitive Potassium Channel 査読有り

    Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

    PLOS ONE　8　(2)　e56342　2013年2月

    DOI： 10.1371/journal.pone.0056342 　

    ISSN：1932-6203

  68. 2SCA-03 電位依存性K+チャネルにおけるイオン透過機構に関する分子動力学的検討(2SCA 最新イオンチャネル1分子科学 : 素過程から疾患克服まで,シンポジウム,日本生物物理学会第51回年会(2013年度))

    笠原 浩太, 城田 松之, 齊藤 俊幸, 近藤 寛子, 木下 賢吾

    生物物理　53　(1)　S93　2013年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.53.S93_6 　

  69. 1P106 計算機シミュレーションによるHv1プロトンチャネルの荷電性残基の影響の検討(03.膜蛋白質,ポスター,日本生物物理学会年会第51回(2013年度))

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

    生物物理　53　(1)　S123　2013年

    出版者・発行元： 一般社団法人 日本生物物理学会

    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

    生物物理　53　(1)　S123　2013年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.53.S123_5 　

  71. Comprehensive Classification and Diversity Assessment of Atomic Contacts in Protein-Small Ligand Interactions 査読有り

    Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

    JOURNAL OF CHEMICAL INFORMATION AND MODELING　53　(1)　241-248　2013年1月

    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

    生物物理　52　S163　2012年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.52.S163_2 　

  73. 3E1046 異なる参照状態を用いた統計ポテンシャルによるタンパク質モデル構造の最適化(蛋白質-構造,口頭発表)

    Shirota Matsuyuki, Kinoshita Kengo

    生物物理　52　S65　2012年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.52.S65_2 　

  74. Prediction of protein-protein complex structures 査読有り

    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年1月1日

    出版者・発行元： 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 査読有り

    Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

    PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　79　(5)　1550-1563　2011年5月

    DOI： 10.1002/prot.22982 　

    ISSN：0887-3585

    eISSN：1097-0134

  76. 3G0948 天然構造のデータのみから構築されたタンパク質モデル構造の絶対的な質の評価法(3G 蛋白質_構造3,日本生物物理学会第49回年会)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    生物物理　51　S129　2011年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.51.S129_2 　

  77. SAHG, a comprehensive database of predicted structures of all human proteins 査読有り

    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年1月

    DOI： 10.1093/nar/gkq1057 　

    ISSN：0305-1048

  78. 3P026 統計ポテンシャルを用いたタンパク質構造の天然らしさの推定(蛋白質-構造,第48回日本生物物理学会年会)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    生物物理　50　(2)　S149　2010年

    出版者・発行元： 一般社団法人 日本生物物理学会

    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. 査読有り

    Shirota, Matsuyuki Ishida, Takashi Kinoshita, Kengo

    Genome Inform　23　(1)　149-158　2009年10月

    出版者・発行元： 1

    ISSN：0919-9454

  80. Analyses on hydrophobicity and attractiveness of all-atom distance-dependent potentials 査読有り

    Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

    PROTEIN SCIENCE　18　(9)　1906-1915　2009年9月

    DOI： 10.1002/pro.201 　

    ISSN：0961-8368

  81. 1P-018 蛋白質立体構造予測のためのメタスコアの開発(蛋白質-構造,第47回日本生物物理学会年会)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    生物物理　49　S66　2009年

    出版者・発行元： 一般社団法人 日本生物物理学会

    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 査読有り

    Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

    PROTEIN SCIENCE　17　(9)　1596-1602　2008年9月

    DOI： 10.1110/ps.035592.108 　

    ISSN：0961-8368

  83. 1P-012 蛋白質サイズが統計ポテンシャルに与える影響(蛋白質・構造(1),第46回日本生物物理学会年会)

    Shirota Matsuyuki, Ishida Takashi, Kinoshita Kengo

    生物物理　48　S22　2008年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.48.S22_5 　

  84. 1P005 ドメインサイズの残基出現頻度と埋もれやすさに与える影響(蛋白質(構造・構造機能相関),口頭発表,第45回日本生物物理学会年会)

    城田 松之, 石田 貴士, 木下 賢吾

    生物物理　47　S24　2007年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.47.S24_4 　

  85. 2P060 タンパク質AMP結合部位の構造多様性(蛋白質(構造・構造機能相関),ポスター発表,第45回日本生物物理学会年会)

    岡本 恵, 土屋 裕子, 城田 松之, 木下 賢吾

    生物物理　47　S128　2007年

    出版者・発行元： 一般社団法人 日本生物物理学会

    DOI： 10.2142/biophys.47.S128_1 　

  86. Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions 査読有り

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

    GENOME RESEARCH　14　(9)　1711-1718　2004年9月

    DOI： 10.1101/gr.2435604 　

    ISSN：1088-9051

  87. Large-scale collection and characterization of promoters of human and mouse genes 査読有り

    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年

    出版者・発行元： 4

    ISSN：1386-6338

︎全件表示 ︎最初の5件までを表示

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年2月

    出版者・発行元： (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年

  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年6月

    出版者・発行元： (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年

  5. アンキリンが生体膜に相互作用する構造基盤

    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年

    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年

  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年

    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年

  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年

  10. A study of dynamics of palmitoylated Ankyrin-G around a lipid bilayer by coarse-grained simulations 査読有り

    Kondo XH, Fujiwara Y, Shirota M, Kinoshita K

    Journal of Physiological Sciences　67　(Supplement1)　S43　2017年

  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年12月

    出版者・発行元： (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年9月

    出版者・発行元： (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年12月

    出版者・発行元： (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年

  15. 血漿プロテオームによる大規模住民コホート研究

    加藤 恭丈, 小柴 生造, 五十嵐 和彦, 山本 雅之, 田邉 修, 蝦名 真行, 城田 松之, 元池 育子, 木下 賢吾, 工藤 久智, 信國 宇洋, 峯岸 直子, 三枝 大輔

    日本プロテオーム学会大会要旨集　2015　(0)　62-62　2015年

    出版者・発行元： 日本プロテオーム学会（日本ヒトプロテオーム機構）

    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年12月

    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年10月

    出版者・発行元： (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年7月7日

  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年

    ISSN： 2186-7976

  20. 大規模コホートにおける血漿プロテオーム解析サンプルの標準化

    加藤 恭丈, 蝦名 真行, 城田 松之, 木下 賢吾, 五十嵐 和彦, 田邊 修

    日本プロテオーム学会大会要旨集　2014　(0)　111-111　2014年

    出版者・発行元： 日本プロテオーム学会（日本ヒトプロテオーム機構）

    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年

    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年

    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年8月

    ISSN： 0961-8368

  24. タンパク質におけるアミノ酸ペアの出現頻度への制約の解析

    城田 松之, 木下 賢吾

    研究報告バイオ情報学（BIO）　2012　(18)　1-2　2012年3月21日

    出版者・発行元： 一般社団法人情報処理学会

    ISSN： 0919-6072

    詳細を見る 詳細を閉じる

    天然タンパク質のアミノ酸配列にはその構造・機能を維持するために様々な制約が課せられている．この制約を明らかにするため，本研究ではタンパク質の配列上できまった残基間隔で出現するアミノ酸残基ペアの出現傾向について統計的に解析を行った．その結果，同じアミノ酸の局所での出現頻度は天然変性タンパク質において高いこと，また，異なるアミノ酸からなるペアの頻度はその順番に大きく影響を受けることが分かった．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年

  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年

  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年

  28. タンパク質におけるアミノ酸ペアの出現頻度への制約の解析

    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年

    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年

  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年

  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年

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 13

  1. 蛋白質立体構造予測手法の開発 競争的資金

    2006年4月 ～ 継続中

  2. DNA・RNA-タンパク質複合体構造に基づくゲノム制御領域変異の効果予測と検証

    城田 松之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2022年4月1日 ～ 2025年3月31日

  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

    2022年4月1日 ～ 2025年3月31日

  4. がんの中心体制御異常の統合的理解による新たな中心体標的療法の開発

    千葉 奈津子, 城田 松之, 大塚 慧, 吉野 優樹, 渡部 剛

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2019年4月1日 ～ 2022年3月31日

    詳細を見る 詳細を閉じる

    中心体は微小管形成中心として機能し、分裂期には紡錘体極として娘細胞への均等な染色体分配を担う。我々は、遺伝性乳がん卵巣がん症候群の原因遺伝子産物であるBRCA1が、BRCA1結合分子BARD1、OLA1、RACK1とともに、分裂期キナーゼであるAurora AやPLK1の中心体局在や活性を制御して、中心体の複製機構とDNA損傷後の中心体数の増加において重要な働きをすることを明らかにした。また、これらの分子のがん由来の変異や発現量の異常が中心体複製の異常を引き起こし、中心体数の増加を起こすことを示し、これらの中心体複製機構の破綻が発がんに関与することを明らかにした。

  5. マイクロエクソンに注目した脳と個性の発現に関する多階層情報解析

    城田 松之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

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

    研究機関：Tohoku University

    2019年4月1日 ～ 2021年3月31日

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    マイクロエクソンは3から27塩基程度の短いエクソンであり、選択的スプライシングにより組織や発達段階特異的にタンパク質に数残基の挿入を生じることで遺伝子の機能を調節する。マイクロエクソンは特に脳で選択的に取り込まれ、神経組織の正常な発達に必要であることが知られているが、細胞レベルでの調節やその調節の個人差についてはよくわかっていない。今年度は前年度までの研究をさらに推進し、マイクロエクソンの調節について公共のデータを用いた情報科学的解析を行った。脳組織でのマイクロエクソンの細胞ごとの発現調節については、公開されているRNA-seqデータを用いて解析を行い、神経組織特異的な取り込みは細胞レベルでは主にニューロン特異的なものであること、また取り込みがスイッチ用に2峰性で切り替わることがわかった。一方、多くの脳一細胞RNA-seqデータはmRNAの3'側のみを用いたものであり、エクソン接合部のリードが含まれないことが多く、解析に適さないことがわかった。 また、マイクロエクソンの調節についての個人差を調べるためにヨーロッパ系およびアフリカ系の1000人ゲノム計画参加者の遺伝型とリンパ芽球の（バルク）RNA-seqデータを用いてスプライシング量的形質座位（sQTL）解析を行った。ヨーロッパ人による探索では10のマイクロエクソンについてsQTLがみられ、このうち6つはアフリカ系集団でも再現された。これらの6つのsQTLはGenotype Tissue Expression (GTEx)データベースで同じ遺伝子の発現量(e)QTLやsQTLであるケースやスプライシング因子U2AF1, U2AF2の結合部位に見られることがわかった。この結果はリンパ球でのものであるが、GTExでの脳組織のデータの利用などで神経組織でのマイクロエクソンの調節の個人差の解析を検討している。

  6. 蛋白質立体構造を用いたゲノム塩基配列変化の機能解析のための情報科学的基盤の構築

    城田 松之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2018年4月1日 ～ 2021年3月31日

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    本研究ではProtein Data Bankのタンパク質立体構造を用いて、タンパク質の疎水性相互作用や立体障害、タンパク質間相互作用、ジスルフィド結合や水素結合、DNAやRNA、イオン、低分子リガンドとの相互作用などの多様な評価指標を用いて、ヒトゲノムの多数の非同義バリアントの中からタンパク質機能に影響を与えるものをゲノムワイドに評価するための情報科学的基盤を構築した。これを用いて既知のバリアントについて評価を行い、またユーザが持つバリアントについてアノテーションを行うウェブシステムを構築した。

  7. 過剰な遺伝子増幅を誘導するシグナル経路を明らかにする

    中山 啓子, 城田 松之, 舟山 亮, 中川 直

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Challenging Research (Exploratory)

    研究機関：Tohoku University

    2018年6月29日 ～ 2020年3月31日

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    ヒトの遺伝子数は通常一細胞あたり２対存在するが、がん細胞では、本来2対であるべき遺伝子の数が増加している事（遺伝子増幅）が頻回に観察されている。しかし、遺伝子増幅がどのように起こるのか、その分子機構について、特に哺乳動物細胞では不明である。私たちはTGF-βシグナルを活性化すると、がん遺伝子myc を含む領域に遺伝子増幅を誘導することを見出した。このシステムを用いて遺伝子増幅の分子機構を明らかにすることを目指した。

  8. ヒストンコードによる転写伸長速度制御機構の解明

    中山 啓子, 城田 松之, 舟山 亮

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2017年4月1日 ～ 2020年3月31日

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    遺伝子からRNAへ転写される領域とその量は、ゲノムDNAが折り畳まれるような構造（クロマチン）の形態によって制御されていると考えられている。このクロマチン構造は、ゲノムDNAのメチル化や、ゲノム領域に結合しているヒストンタンパク質の翻訳後修飾よって決定されると考えられてきた。この研究課題では、ヒストンタンパク質の翻訳後修飾を人為的に変化させたときに、RNAへ転写効率の変化を調べた。

  9. 新規BRCA1結合分子のゲノム安定性維持機構の解明とがん治療法の開発

    千葉 奈津子, 城田 松之, 渡邊 利雄, 吉野 優樹

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2016年4月1日 ～ 2019年3月31日

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    遺伝性乳がん・卵巣がん症候群の原因遺伝子産物であるBRCA1は、BARD1と結合してDNA修復に関与する。我々は、プロテオーム解析で新規BRCA1結合分子として、OLA1とRACK1を同定し、その機能を解析した。その結果、これらの両分子が中心体に局在し、BRCA1、BARD1に直接結合し、中心体複製に重要な働きをすることが明らかになった。RACK1は、BRCA1の中心体局在を制御することも明らかになった。また、これらの分子の発現量の異常やがん由来の変異で中心体複製制御が異常になり、中心体数の異常を来すことが明らかになった。本研究により、BRCA1の新たなゲノム安定性維持機構が解明された。

  10. 大規模シミュレーションとデータベース解析に基づく蛋白質立体構造予測改良法の開発

    城田 松之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Young Scientists (B)

    研究機関：Tohoku University

    2016年4月1日 ～ 2018年3月31日

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    アミノ酸配列からの蛋白質立体構造の予測において構造モデルの精度を向上させることはそのモデルの分子機能の解明や創薬などへの応用可能性を広げる重要な課題である。本研究では既知の蛋白質構造を網羅的に活用することで構造予測改良につなげるデータベースと手法の作成を行った。合わせて、ヒトの蛋白質をターゲットとして、既存の構造とのアラインメントを作成し、構造予測の改良に役立てられるように整備した。さらに、蛋白質立体構造へのマイクロエクソンによるアミノ酸残基挿入やG蛋白質共役型受容体における膜貫通ドメインのアラインメントと変異の統計解析を行って、構造予測の改良を適用する基盤を構築した。

  11. DNA複製による転写とエピゲノム状態の制御の可能性について

    中山 啓子, 城田 松之, 舟山 亮, 細金 正樹

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Challenging Exploratory Research

    研究機関：Tohoku University

    2016年4月1日 ～ 2017年3月31日

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    NIH3T3細胞とMDA-MD-468細胞株にCRISPR/Cas9ライブラリーを導入し、遺伝子ノックアウト細胞群を得た。これらの細胞を、免疫不全マウスの背部皮下に接種し、腫瘍形成を試みた。野生型のNIH3T3細胞は腫瘍形成が見られず、ライブラリー導入細胞を用いても安定した腫瘍形成を観察することができなかった。このことは、NIH3T3細胞では、単一の遺伝子破壊を行った細胞集団が存在しても腫瘍形成には至らないことを示唆している。同様の実験をMDA-MD-468細胞株を用いて行った結果、野生型の細胞に比べて、ライブラリー導入細胞は、腫瘍形成が促進していることが確認された。

  12. H3K27ヒストン修飾によるエンハンサー制御機構の解析

    細金 正樹, 中山 啓子, 舟山 亮, 城田 松之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Young Scientists (B)

    研究機関：Tohoku University

    2015年4月1日 ～ 2017年3月31日

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    細胞のエンハンサー形成におけるヒストン修飾H3K27me3の役割は未だ明らかではない。本研究では、その役割を明らかにするためにH3K27me3欠損K562細胞を用いて各種ヒストン修飾とp300の ChIP-seqならびにRNA-seq解析を実施した。その結果、エンハンサー領域のH3K27me3の減少がエンハンサー活性化の指標であるH3K27acならびにp300の上昇を誘発し、Gene body領域のH3K27me3減少は遺伝子発現を活性化させることが観察された。これらの結果よりH3K27のアセチル化とメチル化の動的な関係によりエンハンサー活性および遺伝子発現が制御されることが明らかとなった。

  13. 蛋白質における埋もれた極性残基の機能評価のためのデータベース構築

    城田 松之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Young Scientists (B)

    研究機関：Tohoku University

    2014年4月1日 ～ 2016年3月31日

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    蛋白質は主に疎水性相互作用によって水溶液中で安定な構造を取るが，蛋白質内部に埋もれた極性残基が作る水素結合などの相互作用も構造と機能に重要な役割を果たす．しかし，これらの埋もれた極性残基は比較的稀な事象ととらえられており，天然の蛋白質における解析は十分に行われてこなかった．本研究ではこれらの埋もれた極性残基をProtein Data Bankから網羅的に集計し，立体構造のパターンと進化的保存についての特徴を解析したものである．これらの成果は蛋白質立体構造予測やデザインに応用できると期待される．

︎全件表示 ︎最初の5件までを表示