Analysis for the pathogenesis and the target molecules of treatment for autism focusing on G-protein coupled receptors and synaptic molecules

• Project/Area Number: 23390275
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• 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)
• Co-Investigator(Renkei-kenkyūsha): NAGATA Kouichi 愛知県心身障害者コロニー発達障害研究所, 神経制御学部, 部長 (50252143) ; MIRI Masato 自治医科大学, 医学部, 講師 (10337347) ; NOZAKI Yasuyuki 自治医科大学, 医学部, 助教 (90281295) ; NAKASHIMA Naomi 自治医科大学, 医学部, 助教 (20337330) ; MONDEN Yukifumi 自治医科大学, 医学部, 講師 (80382951) ; NAGASHIMA Masako 自治医科大学, 医学部, 助教 (70438662) ; JINBO Eriko 自治医科大学, 医学部, 講師 (20291651)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2011: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 自閉症スペクトラム障害 / コピー数多型 / 遺伝子変異 / 足場蛋白 / LIN7 / セクレチン / シナプス / G蛋白結合型受容体 / マイクロアレーCGH / コピー数多型（CNV) / シナプス足場蛋白 / 自閉性障害 / 病因遺伝子 / CNV / 候補遺伝子解析 / モデルマウス / セクレチン受容体

Research Abstract

To detect the relating genes and the treatment of autism spectrum disorder (ASD), we analyzed ASD and intellectual disability patients for copy number variation and candidate gene mutation. Scaffolding proteins such as SHANK3 and LIN7A/B were detected as responsible gene. Lin7a/b were considered to have important role on neuronal development because neuronal cell movement and axon elongation were disturbed by blocking the expression of Lin7a/b in fetal brain. We previously detected gene mutations on the G-protein coupled receptors (GPCRs). Addition to them, mutations on secretin receptor gene that is one of the GPCR were detected. Expression of oxytocin and vasopressin were increased after intra-ventricular injection of secretin. These results indicated that scaffolding proteins and GPCRs closely related to ASD and the molecules relating to them were the targets for the treatment research.

Research Products

• [Journal Article] LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome. (2014)
  • Author(s): Matsumoto A, Mizuno M, Hamada N, Nozaki Y, Jimbo E, Momoi M, Nagata K, Yamagata T
  • Journal Title: PLOS ONE Volume: 9 Issue: 3 Pages: e92695-e92695
  • DOI: 10.1371/journal.pone.0092695
  • Peer Reviewed / Open Access
• [Journal Article] Williams-Beuren syndrome with brain malformation and hypertrophic cardiomyopathy (2014)
  • Author(s): Okamoto N, Yamagata T, Yada Y, Ichihashi K, Matsumoto N, Momoi MY, Mizuguchi T
  • Journal Title: Brain Dev Volume: 36 Issue: 6 Pages: 523-527
  • DOI: 10.1016/j.braindev.2013.07.002
  • Peer Reviewed
• [Journal Article] MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus (2014)
  • Author(s): Saito M, Yamagata T, Shiba Y, Nagashima M, Taniguchi S, Jimbo E, Momoi MY
  • Journal Title: Brain Dev Volume: 36 Issue: 1 Pages: 64-69
  • DOI: 10.1016/j.braindev.2013.01.004
  • Peer Reviewed
• [Journal Article] An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities (2013)
  • Author(s): Matsumoto A, Kuwajima M, Miyake K, Kojima K, Nakashima N, Jimbo EF, Kubota T, Momoi MY, Yamagata T
  • Journal Title: J Hum Genet Volume: 58 Issue: 11 Pages: 755-757
  • DOI: 10.1038/jhg.2013.88
  • Peer Reviewed
• [Journal Article] Clinical correlations of mutations affecting six components of the SWI/SNF complex : Detailed description of 21 patients and a review of the literature (2013)
  • Author(s): Kosho T, Okamoto N, Ohashi H, Yamagata T, Matsumoto N (27人中11番目)
  • Journal Title: Am J Med Genet A Volume: 161 Issue: 6 Pages: 1221-1237
  • DOI: 10.1002/ajmg.a.35933
  • Peer Reviewed
• [Journal Article] Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation (2013)
  • Author(s): Kato M, …Saitsu H.
  • Journal Title: Epilepsia Volume: in press Issue: 7 Pages: 1282-7
  • DOI: 10.1111/epi.12200
  • Peer Reviewed
• [Journal Article] Late-onset Leigh syndrome with myoclonic epilepsy with ragged-red fibers (2013)
  • Author(s): Monden Y, Mori M, Kuwajima M, Goto T, Yamagata T, Momoi MY
  • Journal Title: Brain Dev Volume: 35 Issue: 6 Pages: 582-585
  • DOI: 10.1016/j.braindev.2012.08.006
  • Peer Reviewed
• [Journal Article] Contiguous ABCD1 DXS1357E deletion syndrome : Report of an autopsy case (2013)
  • Author(s): Iwasa M, Yamagata T, Mizuguchi M, Itoh M, Matsumoto A, Hironaka M, Honda A, Momoi MY, Shimozawa N
  • Journal Title: Neuropathology Volume: 33 Issue: 3 Pages: 292-298
  • DOI: 10.1111/j.1440-1789.2012.01348.x
  • Peer Reviewed
• [Journal Article] MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus. (2013)
  • Author(s): Saito M, Yamagata T, Matsumoto A, Shiba Y, Nagashima M, Taniguchi S, Jimbo E, Momoi MY.
  • Journal Title: Brain Dev Volume: 35
  • Peer Reviewed
• [Journal Article] 自閉症 (2013)
  • Author(s): 山形 崇倫
  • Journal Title: 小児神経学の進歩 Volume: 42集
• [Journal Article] Mutation in Parkinson disease-associated, G-protein coupled receptor 37 (GPR37/PaelR) is related to Autism spectrum disorder (2012)
  • Author(s): Fujita-Jimbo E, Yu ZL, Li H, Yamagata T, Mori M, Momoi T, Momoi MY
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Right prefrontal activation as a neuro-functional biomarker for monitoring acute effects of methylphenidate in ADHD children : an fNIRS study (2012)
  • Author(s): Monden Y, Dan I, Dan H, Nagashima M, Tsuzuki D, Kyutoku Y, Gunji Y, Yamagata T, Watanabe E, Momoi MY
  • Journal Title: NeuroImage Clinical Volume: 1 Issue: 1 Pages: 131-40
  • DOI: 10.1016/j.nicl.2012.10.001
  • Peer Reviewed
• [Journal Article] Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination (2012)
  • Author(s): Shimojima K, Okamoto N, Suzuki Y, Saito M, Mori M, Yamagata T, Momoi MY, Hattori H, Okano Y, Hisata K, Okumura A, Yamamoto T
  • Journal Title: J Hum Genet Volume: 57 Issue: 9 Pages: 593-600
  • DOI: 10.1038/jhg.2012.77
  • NAID: 10031057000
  • Peer Reviewed
• [Journal Article] Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome (2012)
  • Author(s): Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N
  • Journal Title: Nat Genet Volume: 44 Issue: 4 Pages: 376-378
  • DOI: 10.1038/ng.2219
  • Peer Reviewed
• [Journal Article] Clinically-oriented monitoring of acute effects of methylphenidate on cerebral hemodynamics in ADHD children using fNIRS (2012)
  • Author(s): Monden Y, Dan H, Nagashima M, Dan I, Kyutoku Y, Okamoto M, Yamagata T, Momoi MY, Watanabe E
  • Journal Title: Clin Neurophysiol Volume: 123 Issue: 6 Pages: 1147-1157
  • DOI: 10.1016/j.clinph.2011.10.006
  • Peer Reviewed
• [Journal Article] Mutation in Parkinson disease-associated, G-protein-coupled receptor 37 (GPR37/PaelR) is related to Autism spectrum disorder. (2012)
  • Author(s): 2. Fujita-Jimbo E, Yu ZL, Li H, Yamagata T, Mori M, Momoi T, Momoi MY
  • Journal Title: PLoS One Volume: 7 Issue: 12 Pages: e51155-e51155
  • DOI: 10.1371/journal.pone.0051155
  • Peer Reviewed
• [Journal Article] Clinically-oriented monitoring of acute effects of methylphenidate on cerebral hemodynamics in ADHD children using fNIRS (2011)
  • Author(s): Monden Y, Dan H, Nagashima M, Dan I, Kyutoku Y, Okamoto M, Yamagata T, Momoi MY, Watanabe E
  • Journal Title: Clin Neurophysiol Volume: (Epub ahead of print)
  • Peer Reviewed
• [Presentation] 自閉症スペクトラム障害の評価 : 統一した評価法の必要性 (2014)
  • Author(s): 山形崇倫, 小島華林, 門田行史
  • Organizer: 第56回日本小児神経学会シンポジウム
  • Place of Presentation: 浜松
• [Presentation] 自閉性障害原因遺伝子変異と小胞体ストレスの関与 (2014)
  • Author(s): 小島華林, 神保恵理子, 松本歩, 山形崇倫, 桃井隆, 桃井真里子
  • Organizer: 第56回日本小児神経学会
  • Place of Presentation: 浜松
• [Presentation] 自閉性障害患者における時計関連遺伝子の変異解析 (2014)
  • Author(s): 松本歩, 楊志亮, 小島華林, 中山一大, 神保恵理子, 岩本禎彦, 永田浩一, 山形崇倫
  • Organizer: 第56回日本小児神経学会
  • Place of Presentation: 浜松
• [Presentation] 自閉性障害原因遺伝子 CADM1 に結合する足場タンパク MUPP1 の遺伝子変異解析 (2014)
  • Author(s): 楊志亮, 小島華林, 神保恵理子, 山形崇倫, 桃井隆, 桃井真里子
  • Organizer: 第56回日本小児神経学会
  • Place of Presentation: 浜松
• [Presentation] Contribution of Scaffold proteins to developmental disorder (2013)
  • Author(s): Matsumoto A, Mizuno M, Hamada N, Jimbo EF, Kojima K, Momoi MY, Nagata K, Yamagata T
  • Organizer: The 63rd Annual Meeting for the American Society of Human Genetics
  • Place of Presentation: Boston
• [Presentation] Mutations in Secretin receptor may be related to autism spectrum disorder (2013)
  • Author(s): Kojima K, Yamagata T, Matsumoto A, Jimbo EF, Momoi MY
  • Organizer: The 63rd Annual Meeting for the American Society of Human Genetics
  • Place of Presentation: Boston
• [Presentation] 発達障害患者 CNV 領域におけるシナプス関連分子の解析 (2013)
  • Author(s): 山形崇倫, 松本歩, 永田浩一
  • Organizer: 第55回日本小児神経学会シンポジウム
  • Place of Presentation: 大分
• [Presentation] 発達障害患者 CNV領域におけるシナプス関連分子の解析 (2013)
  • Author(s): 松本歩, 山形崇倫, 野崎靖之, 神保恵理子, 永田浩一, 桃井真里子
  • Organizer: 第55回日本小児神経学会
  • Place of Presentation: 大分
• [Presentation] Contribution of Scaffold proteins to developmental disorder. (2013)
  • Author(s): Matsumoto A, Mizuno M, Hamada N, Jimbo EF, Kojima K, Momoi MY, Nagata K, Yamagata T.
  • Organizer: The 63rd Annual Meeting for the American Society of Human Genetics.
  • Place of Presentation: Boston
• [Presentation] Mutations in Secretin receptor may be related to autism spectrum disorder. (2013)
  • Author(s): Kojima K, Yamagata T, Matsumoto A, Jimbo EF, Momoi MY
  • Organizer: The 63rd Annual Meeting for the American Society of Human Genetics.
  • Place of Presentation: Boston
• [Presentation] 発達障害患者CNV領域におけるシナプス関連分子の解析. (2013)
  • Author(s): 山形崇倫、松本歩、永田浩一
  • Organizer: 第55回日本小児神経学会シンポジウム
  • Place of Presentation: 大分
• [Presentation] 発達障害患者CNV領域におけるシナプス関連分子の解析. (2013)
  • Author(s): 松本歩、山形崇倫、野崎靖之、神保恵理子、永田浩一、桃井真里子
  • Organizer: 第55回日本小児神経学会
  • Place of Presentation: 大分
• [Presentation] A NDUFA1 mutation in a boy with mitochondrial complexIdeficiency. (2013)
  • Author(s): Miyauchi A, Monden Y, Mori M, Sugie H, Osaka H, Murayama K, Ohtake A, Yamagata T
  • Organizer: The 55th Annual Meeting of The Japanese Society for Inherited Metabolic Diseases(JSIMD)
  • Place of Presentation: Tokyo
• [Presentation] RPS6KA3 の重複を認めた軽度知的障害男児例 (2012)
  • Author(s): 松本歩, 山形崇倫, 桑島真理, 神保恵理子, 桃井真里子
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] Cadm1 変異を持つ自閉性障害患者のリンパ芽球を用いた小胞体ストレス感受性についての検討 (2012)
  • Author(s): 小島華林, 松本歩, 楊志亮, 神保恵理子, 山形崇倫, 桃井真里子
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] Mutation in Secretin receptor gene in Autism spectrum disorder and genes regulated by secretin in the brain (2012)
  • Author(s): Kojima K, Yamagata T, Matsumoto A, Saito M, Jimbo EF, Momoi MY
  • Organizer: The 62rd Annual Meeting for the American Society of Human Genetics
  • Place of Presentation: San Francisco
• [Presentation] Interstitial Deletion 12(q21.2-q21.33) in a Boy with Facial Dysmorphism and Mental Retardation (2012)
  • Author(s): Matsumoto A, Yamagata T, Nozaki Y, Jimbo EF, Momoi MY
  • Organizer: The 62rd Annual Meeting for the American Society of Human Genetics
  • Place of Presentation: San Francisco
• [Presentation] Mutation in the gene encoding Secretin Recepor is associated with autism spectrum disorder (2012)
  • Author(s): Kojima K, Yamagata T, Matsumoto A, Jimbo E, Momoi MY
  • Organizer: The 62th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Francisco
• [Presentation] Interstitial Deletion 12(q21.2-q21.33) in a Boy with Facial Dysmorphism and Menta Retardation (2012)
  • Author(s): Matsumoto A, Yamagata T, Nozaki Y, Jimbo E, Momoi MY
  • Organizer: The 62th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Francisco
• [Presentation] Cadm1遺伝子変異をもつ自閉性障害患者のリンパ芽球を用いた小胞体ストレス感受性についての検討 (2012)
  • Author(s): 小島華林、松本歩、楊志亮、神保恵理子、山形崇倫、桃井眞里子
  • Organizer: 日本人類遺伝学会 第57回大会
  • Place of Presentation: 東京
• [Presentation] RPS6KA3の重複を認めた軽度知的障害男児例 (2012)
  • Author(s): 松本歩、山形崇倫、桑島真理、神保恵理子、桃井真里子
  • Organizer: 日本人類遺伝学会 第57回大会
  • Place of Presentation: 東京
• [Presentation] Duplication of GPC3 in the boy with growth retardation and developmental delay (2011)
  • Author(s): Nakashima N, Yamamgata T, Saito M, Nozaki Y, Momoi MY
  • Organizer: The 61st Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2011-11-14
• [Presentation] Deletion of MAOA and MAOB in male siblings with severe mental retardation and autistic phenotype (2011)
  • Author(s): Saito M, Yamagata T, Shiba Y, Nakashima N, Nagashima M, Jimbo E, Momoi MY
  • Organizer: The 61st Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2011-11-13
• [Presentation] 自閉性障害患者に見いだされた変異蛋白による小胞体ストレスと分子病態との関係 (2011)
  • Author(s): 神保恵理子、山形崇倫、桃井真里子
  • Organizer: 第53回日本小児神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-05-27
• [Presentation] Deletion of MAOA and MAOB in male siblings with severe mental retardation and autistic phenotype (2011)
  • Author(s): Saito M, Yamagata T, Shiba Y, Nakashima N, Nagashima M, Jimbo E, Momoi MY
  • Organizer: The 62rd Annual Meeting for the American Society of Human Genetics
  • Place of Presentation: Montreal