Effects of growth-associated protein 43 (GAP43) on neurodevelopmental disorders

• Project/Area Number: 17K16371
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Niigata University
• Principal Investigator: Inoue Emiko 新潟大学, 医歯学総合研究科, 客員研究員 (80726323)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 自閉症 / GAP-43 / シナプス / ハイコンテントスクリーニング / 神経発達障害 / GAP43 / 自閉スペクトラム症 / 機能的リン酸化部位 / 統合失調症

Outline of Final Research Achievements

We identified a rare, functionally harmful missense mutation (rs561268447) identified by exon sequencing of the GAP-43 gene in DNA samples from human autistic patients. An association analysis of rs561268447 was performed on the mutation in 568 autistic patients, 1,473 schizophrenia patients, and 10,127 controls. However, no significant association with the disease was confirmed (Arta et al., 2021). We stained Hela cells introduced with the mutation at the rs561268447 with anti-GAP43 antibody. As a result, the expression of GAP43 around the nucleus was lower in the mutagenesis cells than in the wild-type GAP43-introduced cells.

Academic Significance and Societal Importance of the Research Achievements

自閉症ヒト患者のDNAサンプルにおけるGAP-43遺伝子のエクソンシーケンスにより同定したin silico解析（Polyphen-2およびSIFT）において機能的に有害と判定された稀なミスセンス変異（rs561268447）は、一般集団おいて自閉症および統合失調症のリスクとなることは示すことはできなかったが、少なくとも自閉症の一部の集団でのリスクとなることや細胞レベルで異常を起こす可能性を示した。本研究成果は自閉症の病態研究や治療開発推進の一助となると考えられる。

Research Products

• [Journal Article] Resequencing and association analysis of GAP43 with autism spectrum disorder and schizophrenia in a Japanese population (2021)
  • Author(s): Arta Reza K.、Watanabe Yuichiro、Inoue Emiko、Nawa Yoshihiro、Morikawa Ryo、Egawa Jun、Kushima Itaru、Igeta Hirofumi、Hoya Satoshi、Sugimoto Atsunori、Tanra Andi J.、Ozaki Norio、Someya Toshiyuki
  • Journal Title: Research in Autism Spectrum Disorders Volume: 82 Pages: 101729-101729
  • DOI: 10.1016/j.rasd.2021.101729
  • Peer Reviewed / Open Access
• [Journal Article] Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. (2018)
  • Author(s): Okazaki S, Hishimoto A, Otsuka I, Watanabe Y, Numata S, Boku S, Shimmyo N, Kinoshita M, Inoue E, Ohmori T, Someya T, Sora I.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry. Volume: 83 Pages: 33-41
  • DOI: 10.1016/j.pnpbp.2018.01.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rare PDCD11 variations are not associated with risk of schizophrenia in Japan (2017)
  • Author(s): Hoya Satoshi、Watanabe Yuichiro、Hishimoto Akitoyo、Nunokawa Ayako、Kaneko Naoshi、Muratake Tatsuyuki、Shinmyo Naofumi、Otsuka Ikuo、Okuda Shujiro、Inoue Emiko、Igeta Hirofumi、Shibuya Masako、Egawa Jun、Orime Naoki、Sora Ichiro、Someya Toshiyuki
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 71 Issue: 11 Pages: 780-788
  • DOI: 10.1111/pcn.12549
  • Peer Reviewed / Open Access
• [Journal Article] Rare FBOX18 variations and risk of schizophrenia: whole-exome sequencing in two parent-affected offspring trios followed by resequencing and case-control studies. (2017)
  • Author(s): Hoya S, Watabe Y, Hishimoto A, Nunokawa A, Inoue E, Igeta H, Otsuka I, Shibuya M, Egawa J, Sora I, Someya T
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 印刷中 Issue: 8 Pages: 562-568
  • DOI: 10.1111/pcn.12526
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 自閉スペクトラム症多発罹患家系の全エクソームシークエンスおよびフォローアップ研究 (2017)
  • Author(s): 井上絵美子, 渡部雄一郎, 江川純, 杉本篤言, 布川綾子, 澁谷雅子, 井桁裕文, 染矢俊幸
  • Journal Title: 精神神経学雑誌 Volume: 119(1) Pages: 3-8
• [Presentation] 無症候性に進行し躁症状で発見された神経梅毒の一例 (2019)
  • Author(s): 井上絵美子, 谷卓, 小澤鉄太郎, 寺島健史, 湯川尊行, 有波浩, 恩田啓伍, 染矢俊幸
  • Organizer: 第115回日本精神神経学会
• [Presentation] Resequencing of the SETD1A gene in Japanese patients with schizophrenia (2018)
  • Author(s): Hoya S, Igeta H, Watanabe Y, Nunokawa A, Inoue E, Shibuya M, Egawa J, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Whole-exome sequencing in a consanguineous multiplex family with schizophrenia and a case-control study. (2018)
  • Author(s): Igeta H, Watanabe Y, Hoya S, Ikeda M, Hishimoto A, Nunokawa A, Inoue E, Sora I, Iwata N, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Rare FBXO18 variations and risk of schizophrenia. (2018)
  • Author(s): Watanabe Y, Hoya S, Hishimoto A, Nunokawa A, Inoue E, Igeta H, Otsuka I, Shibuya M, Sora I, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research