Genetic analysis for autism spectrum disorder and intellectual disability focusing on synaptic network abnormality

• Project/Area Number: 16K09995
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Jichi Medical University
• Principal Investigator: Yamagata Takanori 自治医科大学, 医学部, 教授 (00239857)
• Research Collaborator: Matsumoto Ayumi ; Goto Masahide ; Kojima Karin ; Jimbo Eriko ; Nagata Ko-ichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 自閉スペクトラム症 / シナプス / 概日リズム関連遺伝子 / マイクロRNA / マイクロアールエヌエー / PER3 / 染色体微小変異 / マイクロアレーCGH / 染色体微小変化 / 概日リズム / 自閉症スペクトラム / 染色体コピー数多型 / NR!D! / 学習障害 / シナプス足場蛋白

Outline of Final Research Achievements

To detect the pathogenic gene mutations for autism spectrum disorder (ASD) and their function, we analyzed patients samples by aCGH, candidate gene sequence and exome sequence. Several copy number variations (CNVs) were detected and candidate genes were selected. Among them, several genes such as GAS2, and also, microRNAs such as Mir935 were considered to relate with ASD. Addition to that, we detected several mutations on circadian relevant genes. Among them, Nr1d1 and Per3 were analyzed firstly. By intra-utero gene knock down of each gene by RNAi electropolation, neuronal migration and neurite elongation were disturbed. Addition to the mutations in ASD patients, these genes were considered to relate with ASD through the function on synaptic and neural network formation.
And we started the clinical study of a drug that relate the oxytocin function for ASD patients.

Academic Significance and Societal Importance of the Research Achievements

学術的意義として、ASDの病因となるコピー数多型、遺伝子変異、マイクロRNAなどを同定したことが挙げられる。特に、概日リズム関連遺伝子がASD患者で変異の頻度が高いことを示したことは意義が大きい。その中で、NR1D1とPER3が、概日リズム形成以外に神経形成にも重要な機能を有していることは知られていなかったことであり、概日リズム形成の解明研究に対しても重要な結果である。ASDの病因、病態が明らかになることは、患者の診断、予後判定、さらに治療法開発に重要である。現在、治療候補薬の臨床研究に着手しており、治療効果が示されれば、社会的意義も大きい。

Research Products

• [Journal Article] Role of Per3, a circadian clock gene, in embryonic development of mouse cerebral cortex.? (2019)
  • Author(s): Noda M, Iwamoto I, Tabata H, Yamagata T, Ito H, Nagata K.
  • Journal Title: Sci. Rep. Volume: 9 Issue: 1 Pages: 5874-5874
  • DOI: 10.1038/s41598-019-42390-9
  • Peer Reviewed / Open Access
• [Journal Article] Rapid progression of a walking disability in a 5-year-old boy with a CLN6 mutation (2019)
  • Author(s): Matsumoto Ayumi、Nagashima Masako、Iwama Kazuhiro、Mizuguchi Takeshi、Makino Shinji、Ikeda Takahiro、Muramatsu Kazuhiro、Matsumoto Naomichi、Yamagata Takanori、Osaka Hitoshi
  • Journal Title: Brain and Development Volume: 印刷中 Issue: 8 Pages: 726-730
  • DOI: 10.1016/j.braindev.2019.04.009
  • Peer Reviewed
• [Journal Article] The presence of diminished white matter and corpus callosal thinning in a case with a SOX9 mutation. (2018)
  • Author(s): Matsumoto, A. Imagawa, E. Miyake, N. Ikeda, T. Kobayashi, M. Goto, M. Matsumoto, N. Yamagata, T. Osaka, H.
  • Journal Title: Brain and Development Volume: 40 Issue: 4 Pages: 325-9
  • DOI: 10.1016/j.braindev.2017.09.002
  • Peer Reviewed
• [Journal Article] A patient with early myoclonic encephalopathy (EME) with a de novo KCNQ2 mutation (2018)
  • Author(s): Kojima K、Shirai K、Kobayashi M、Miyauchi A、Saitsu H、Matsumoto N、Osaka H、Yamagata T
  • Journal Title: Brain and Development Volume: 40 Issue: 1 Pages: 69-73
  • DOI: 10.1016/j.braindev.2017.06.004
  • Peer Reviewed
• [Journal Article] Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C (2017)
  • Author(s): Kodachi T、Matsumoto Shizuko、Mizuguchi Masashi、Osaka Hitoshi、Kanai Nobuyuki、Nanba Eiji、Ohno Kousaku、Yamagata Takanori
  • Journal Title: Neuropathology Volume: 37 Issue: 5 Pages: 426-430
  • DOI: 10.1111/neup.12380
  • Peer Reviewed
• [Journal Article] Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome (2017)
  • Author(s): Nakamura Sachie、Osaka Hitoshi、Muramatsu Shin-ichi、Takino Naomi、Ito Mika、Aoki Shiho、Jimbo Eriko F.、Shimazaki Kuniko、Onaka Tatsushi、Ohtsuki Sumio、Terasaki Tetsuya、Yamagata Takanori
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 10 Pages: 67-74
  • DOI: 10.1016/j.ymgmr.2016.12.008
  • Peer Reviewed
• [Journal Article] Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders. (2017)
  • Author(s): Goto, M., Mizuno, M., Matsumoto, A., Yang, Z., Jimbo, E.F., Tabata, H., Yamagata, T., Nagata, K.-I.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 43945-43945
  • DOI: 10.1038/srep43945
  • Peer Reviewed / Open Access
• [Journal Article] Association of Oxytocin and Parental Prefrontal Activation during Reunion with Infant: A Functional Near-Infrared Spectroscopy Study (2017)
  • Author(s): Ito Jun、Fujiwara Takeo、Monden Yukifumi、Yamagata Takanori、Ohira Hideki
  • Journal Title: Frontiers in Pediatrics Volume: 5 Pages: 271-271
  • DOI: 10.3389/fped.2017.00271
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of Autistic Traits in Children Aged 2 to 4.5 Years With the Preschool Version of the Social Responsiveness Scale (SRS-P): Findings from Japan. (2017)
  • Author(s): Stickley A, Tachibana Y, Hashimoto K, Haraguchi H, Miyake A, Morokuma S, Nitta H, Oda M, Ohya Y, Senju A, Takahashi H, Yamagata T, Kamio Y.
  • Journal Title: Autism Res. Volume: 3 Issue: 5 Pages: 852-865
  • DOI: 10.1002/aur.1742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders. (2016)
  • Author(s): Inaguma Y, Matsumoto A, Noda M, Tabata H, Maeda A, Goto M, Usui D, Jimbo EF, Kikkawa K, Ohtsuki M, Momoi MY, Osaka H, Yamagata T, Nagata KI
  • Journal Title: J Neurochem Volume: 139 Issue: 2 Pages: 245-55
  • DOI: 10.1111/jnc.13832
  • Peer Reviewed
• [Presentation] 自閉スペクトラム症児に対するアレイCGH解析によるMicroRNAの検討 (2018)
  • Author(s): 後藤昌英、松本歩、神保恵理子、小坂仁、大橋圭、齋藤伸治、山形崇倫
  • Organizer: 第60回日本小児神経学会学術集会
• [Presentation] 急速に歩行障害が進行したCLN6変異を有する神経セロイドリポフスチン症の5歳男児例 (2018)
  • Author(s): 松本歩、小坂仁、長嶋 雅子、岩間 一浩、水口 剛、池田 尚広、村松 一洋、松本 直通、山形崇倫
  • Organizer: 第60回日本小児神経学会学術集会
• [Presentation] 自閉症スペクトラム障害児に対するアレイCGH解析での検討 (2017)
  • Author(s): 後藤昌英、松本歩、神保恵理子、小坂仁、大橋圭、齋藤伸治、山形崇倫
  • Organizer: 第59回日本小児神経学会総会
• [Presentation] Role of a circadian-relevant gene, NR1D1, in brain development: possible involvement in the pathophysiology of autism spectrum disorder (2017)
  • Author(s): Masahide Gotoa, Makoto Mizunob, Ayumi Matsumotoa, Zhiliang Yanga , Eriko F Jimboa, Hidenori Tabata, Hitoshi Osaka, Koh-ichi Nagata, Takanori Yamagata
  • Organizer: 2017 International Meeting for Autism Research
  • Int'l Joint Research
• [Presentation] PIK3C3 is responsible gene for epidermal nevus, cataract and learning disorder. (2016)
  • Author(s): Matsumoto A, Inaguma Y, Usui D, Goto M, Jimbo EF, Tabata H, Maeda A, Kikkawa K, Momoi MY, Osaka H, Nagata KI. Yamagata T
  • Organizer: American Society of Human Genetics 2016 Annual meeting
  • Place of Presentation: Vancouver
  • Year and Date: 2016-10-18
  • Int'l Joint Research