ゲノムブロック異常と精神神経疾患発症素因の解明

• Project/Area Number: 20023024
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Yokohama City University
• Principal Investigator: 松本 直通 Yokohama City University, 医学研究科, 教授 (80325638)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥7,600,000 (Direct Cost: ¥7,600,000); Fiscal Year 2009: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 2008: ¥3,800,000 (Direct Cost: ¥3,800,000)
• Keywords: 脳神経疾患 / ゲノム / マイクロアレー / 遺伝子

Research Abstract

背景:マイクロアレーの解析技術の進展で、これまで未発見の精神神経疾患関連・関連遺伝子単離が可能となると期待されている。
研究目的:本研究は、機能性精神神経疾患および精神遅滞関連症候群を対象とし、ゲノムブロック異常(重複や欠失に代表されるゲノム微細構造異常)に焦点をあて、高精度ゲノムマイクロアレーを用いて網羅的に検出・カタログ化し、精神神経疾患素因・感受性遺伝子の同定と発症機序の解明を行うことを目的とする。新たな対象疾患に自閉症を加えた。
結果:[症例集積状況]20年度から新たに解析対象とした自閉症に関しては大阪大学医学研究科精神医学・橋本亮太先生の研究協力を得て、35例を既に集積した。
[ゲノム異常の同定と検証]自閉症35症例におけるAffymetrix社SNP6.0(185万オリゴDNAを全ゲノムに配置)を用いたCNV解析を行った。異常検出部位は患者細胞ペレットと当該クローンDNAを用いてFISH、あるいはゲノムDNAを用いて定量PCRで欠失や重複の検証を行っている。
[精神遅滞症候群における責任遺伝子単離]West症候群の新規責任遺伝子EIEE2(仮称)の単離に成功した(論文投稿中)。EIEE2もSTXBP1と同様チャネルや受容体とは全く異なる分子で、てんかんの発症機構として極めてユニークな発症機構が疑われた。
考察:新たに解析対象とした自閉症症例の解析が進行中である。多数のCNVが検出されており、その病的意義の検証を行っていく必要がある。West症候群の新しい責任遺伝子の単離に成功し、精神神経疾患のCNVを含むゲノム構造解析の有効性が明らかとなった。

Research Products

• [Journal Article] Gene analysis of Marfan syndrome. (2009)
  • Author(s): Matsumoto N
  • Journal Title: Proceedings of VIII annual international symposium on advances in understanding aortic diseases. 1 Pages: 23-27
• [Journal Article] Severity and progression rate of cerebellar ataxia in 16q-linked autosomal dominant cerebellar ataxia (16q-ADCA) in the endemic Nagano area of Japan. (2009)
  • Author(s): Yoshida K, others, Matsumoto N, others
  • Journal Title: Cerebellum 8 Pages: 46-51
  • Peer Reviewed
• [Journal Article] A locus for Ophthalmo-acromelic syndrome mapped to 10p11.23. (2009)
  • Author(s): Hamanoue H, others, Matsumoto N
  • Journal Title: Am J Med Genet 149A Pages: 336-342
  • Peer Reviewed
• [Journal Article] Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome. (2009)
  • Author(s): Kuniba H, others, Matsumoto N, others.
  • Journal Title: J Hum Genet 54 Pages: 304-309
  • Peer Reviewed
• [Journal Article] Characterization of the complex 7q21.3 rearrangement in a patient with bilateral split foot malformation and hearing loss. (2009)
  • Author(s): Saitsu H, others, Matsumoto N.
  • Journal Title: Am J Med Genet 149A Pages: 1224-1230
  • Peer Reviewed
• [Journal Article] Identification of Independent APP Locus Duplication in Japanese Patients with E arly-Onset Alzheimer's Disease. (2009)
  • Author(s): Kasuga K, others, Matsumoto N , others.
  • Journal Title: J Neurol Neurosurg Psychiatry 80 Pages: 1050-1052
  • Peer Reviewed
• [Journal Article] Gene screening of 104 patients with congenital heart disease revealed a fresh GATA4 mutation in atrial septal defect. (2009)
  • Author(s): Hamanoue H, others, Matsumoto N.
  • Journal Title: Cardiol Young 19 Pages: 482-485
  • Peer Reviewed
• [Journal Article] A girl with Down syndrome and partial trisomy for 21pter-q22.13 : A clue to narrow the Down syndrome critical region (2008)
  • Author(s): Sato D, others, Matsumoto N, others
  • Journal Title: Am J Med Genet 146A Pages: 124-127
  • Peer Reviewed
• [Journal Article] Decreased serum dependence in the growth of NIH3T3 cells from the overexpression of human nuclear receptor-binding SET-domain-containing protein (NSD1) or fission yeast su(var)3-9, enhancer-of-zeste, trithorax 2(SET2) (2008)
  • Author(s): Yamada-Okabe T, Matsumoto N
  • Journal Title: Cell Biochemistry and Function 26 Pages: 146-150
  • Peer Reviewed
• [Journal Article] Two New Cases of Pure lq Terminal Deletion Presenting With Brain Malformations (2008)
  • Author(s): Hiraki Y, others, Matsumoto N
  • Journal Title: Am J Med Genet 146A Pages: 1241-1247
  • Peer Reviewed
• [Journal Article] Two patients with atypical interstitial deletions of 8p23.1 : Mapping of phenotypical traits (2008)
  • Author(s): Paez M, others, Matsumoto N, others
  • Journal Title: Am J Med Genet 146A Pages: 1158-1165
  • Peer Reviewed
• [Journal Article] Craniosynostosis in a patient with a de novo 15q15-q22 deletion (2008)
  • Author(s): Hiraki Y, others, Matsumoto N
  • Journal Title: Am J Med Genet 146A Pages: 1462-1465
  • Peer Reviewed
• [Journal Article] Alu-related 5q35 microdeletions in Sotos syndrome (2008)
  • Author(s): Mochizuki J, others, Matsumoto N
  • Journal Title: Clin Genet 74 Pages: 384-391
  • Peer Reviewed
• [Journal Article] De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy (2008)
  • Author(s): Saitsu H, others, Matsumoto N
  • Journal Title: Nat Genet 40 Pages: 782-788
  • Peer Reviewed
• [Journal Article] A Case of Schizophrenia with Chromosomal Microdeletion of 17p11.2 Containing a Myelin-Related Gene PMP22 (2008)
  • Author(s): Ozeki Y, others, Matsumoto N, Kunugi H
  • Journal Title: The Open Psychiatry Journal 2 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Lack of C20orfl33 and FLRT3 mutations in 43 patients with Kabuki syndrome in Japan (2008)
  • Author(s): Kuniba H, others, Matsumoto N, others
  • Journal Title: J Med Genet 45 Pages: 479-480
  • Peer Reviewed
• [Journal Article] CDKL5 disruption by t(X; 18) in a girl with West syndrome (2008)
  • Author(s): Nishimura A, others Matsumoto N
  • Journal Title: Clin Genet 74 Pages: 288-290
  • Peer Reviewed
• [Journal Article] No mutation in RAS-MAPK pathway genes in 30 patients with Kabuki syndrome (2008)
  • Author(s): Kuniba H, others, Matsumoto N, Niikawa N
  • Journal Title: Am J Med Genet 146A Pages: 1893-1896
  • Peer Reviewed
• [Journal Article] Microarray comparative genomic hybridization analysis of 59 patients with schizophrenia (2008)
  • Author(s): Mizuguchi T, others, Matsumoto N
  • Journal Title: J Hum Genet 53 Pages: 914-919
  • Peer Reviewed
• [Journal Article] Bilateral perisylvian polymicrogyria, periventricular nodular heterotopia, and left ventricular noncampaction in a girl with 10.5-11.1 Mb terminal deletion of 1p36 (2008)
  • Author(s): Saito S, others, Matsumoto N, others
  • Journal Title: Am J Med Genet 146A Pages: 2891-2897
  • Peer Reviewed
• [Presentation] STXBP1 mutations in severe infantile epilepsies with suppression-burst pattern (2009)
  • Author(s): Matsumoto N
  • Organizer: The international symposium in the 9^<th> Annual Meeting of the East Asian Union of Human Genetic Society
  • Place of Presentation: ソウル・韓国
  • Year and Date: 2009-11-19
• [Presentation] Evaluation of Affymetri^[○!R] Cytogenetics Whole-Genome Array Using Clinical Sample. (2009)
  • Author(s): Matsumoto N
  • Organizer: Asin Cytogeentics Community Workshop (by Affy metrix Inc.)
  • Place of Presentation: ホノルル・ハワイ
  • Year and Date: 2009-10-24
• [Presentation] 年齢依存性てんかん性脳症の最近の話題 (2009)
  • Author(s): 松本直通
  • Organizer: 第51回日本小児神経学会関東地方会
  • Place of Presentation: 横浜市開港記念会館・横浜
  • Year and Date: 2009-09-19
• [Presentation] 疾患ゲノム解析の新戦略 (2009)
  • Author(s): 松本直通
  • Organizer: 第44回日本小児腎臓病学会学術集会
  • Place of Presentation: 一橋記念講堂・東京
  • Year and Date: 2009-06-26
• [Presentation] De novo mutations in STXBP1 cause early infantile epileptic encephalopathy. (2009)
  • Author(s): Matsumoto N, Saitsu H
  • Organizer: European Human Genetics Conference 2009
  • Place of Presentation: オーストリア・ウィーン
• [Presentation] アレーを用いて疾患遺伝子を単離する (2008)
  • Author(s): 松本直通
  • Organizer: 日本人類遺伝学会第53回大会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-30
• [Presentation] Alu-related 5q35 microdeletions in Sotos syndrome (2008)
  • Author(s): Matsumoto N, Mochizuki J
  • Organizer: European Human Genetics Conference 2008
  • Place of Presentation: スペイン・バルセロナ
• [Presentation] De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy (2008)
  • Author(s): Matsumoto N, others
  • Organizer: The international symposium in the 8^<th> Annual Meeting of the East Asian Union of Human Genetic Society
  • Place of Presentation: 札幌
• [Presentation] Alu-related 5q35 microdeletions in Sotos syndrome (2008)
  • Author(s): Matsumoto N, Mochizuki J
  • Organizer: 58th Annual Meeting of American Society of Human Genetics
  • Place of Presentation: アメリカ・ペンシルベニア
• [Patent(Industrial Property Rights)] 大脳白質異常を伴う点頭てんかんの検出方法 (2009)
  • Inventor(s): 松本直通/才津浩智
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 2009-146055
  • Filing Date: 2009-06-19