RIKEN's New Research Center for Brain Science: 脳神経科学研究センター(理研CBS)ウェブサイト

RIKEN BRAIN SCIENCE INSTITUTE (理研BSI)

Faculty Detail / 研究室詳細

神経遺伝研究チーム

シニア・チームリーダー

Gene, Mutations, Epilepsy, Down syndrome

山川  和弘

研究内容

当研究チームでは、てんかん・自閉症・ダウン症などの精神神経疾患の発症機構の解明、診断法・治療法の開発などを目標に、遺伝子に主眼をおいて研究を進めています。てんかんはおよそ100人に一人が発症する疾患で、100をはるかに越える種類が知られており、その多くに遺伝的背景が予想されています。我々は、若年性ミオクローヌスてんかんなどの最も頻度の高いものや重症乳児ミオクロニーてんかんなど重篤で知能障害を伴うものなどの原因遺伝子の同定およびその機能の解析、原因遺伝子ノックアウトなどによるモデル動物の作成、更にそれらを用いた治療法の検討などを進めています。また、てんかんは自閉症との合併率が高い(およそ3割)ことでも知られており、我々はそれらに共通する発症基盤を想定し、それら合併例の全ゲノム解析などによる原因/関連遺伝子の同定や機能解析を進めています。ダウン症はおよそ700人に一人の割合で生まれてくる、最も頻度の高い精神遅滞の原因であり、本来2本であるべき21番染色体が3本になることによって起こります。マウスでは16番染色体の一部がヒト21番染色体に相当しますが、我々はこの領域を3本持ったダウン症モデルマウスを中心にダウン症精神遅滞発症機構の解明を目指して解析を進めています。

主な発表論文 全て表示する

  1. 1

    Bailey JN+, de Nijis L+, Bai D+, Suzuki T+, Miyamoto H, Tanaka M, Patterson C, Lin YC, Medina M, Alonso M, Seratossa J, Duron R, Nguyen V, Wight J, Martinez-Juarez I, Ochoa A, Jara-Prado A, Guilhoto L, Molina Y, Yacubian E, Lopez-Ruiz M, Inoue Y, Kaneko S, Hirose S, Osawa M, Oguni H, Fujimoto S, Grisar T, Stern J, Yamakawa K*, Laykaye B*, Delgado-Escueta A* (+co-first authors, and *co-corresponding authors): "Variant intestinal cell kinase in juvenile myoclonic epilepsy", New Eng J Med , 378, 1018-28 (2018)

  2. 2

    Raveau M, Polygalov D, Boehringer R, Amano K, Yamakawa K*, and McHugh TJ* (*co-corresponding authors).: "Alterations of in vivo CA1 network activity in Dp(16)1Yey Down
syndrome model mice", eLife, 7, e31543 (2018)

  3. 3

    Tatsukawa T, Ogiwara I, Mazaki E, Shimohata A, and Yamakawa K. : "Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells", Neurobiol Dis, 112, 24-34 (2018)

  4. 4

    Raveau M, Shimohata A, Amano K, Miyamoto H, and Yamakawa K. : "DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures", Neurobiol Dis, 110, 180-191 (2017)

  5. 5

    Miyamoto H, Shimohata A, Abe M, Abe T, Mazaki M, Amano K, Suzuki T, Tatsukawa T, Itohara S, Sakimura K, and Yamakawa K. : "Potentiation of excitatory synaptic transmission ameliorates aggression in mice with Stxbp1 haploinsufficiency", Human Molecular Genetics, 26, 4961-4974 (2017)

  6. 6

    Shimohata A, Ishihara K, Hattori S, Miyamoto H, Morishita H, Ornthanalai G, Raveau M, Ebrahim AS, Amano K, Yamada K, Sago H, Akiba S, Mataga N, Murphy NP, Miyakawa T, and Yamakawa K. : "Ts1Cje Down syndrome model mice exhibit environmental stimuli-triggered locomotor hyperactivity and sociability concurrent with increased flux through central dopamine and serotonin metabolism", Exp Neurol, 293, 1-12 (2017)

  7. 7

    Raveau M, Nakahari T, Asada S, Ishihara K, Amano K, Shimohata A, Sago H, and Yamakawa K. : "Brain ventriculomegaly in Down syndrome mice is caused by Pcp4 dose-dependent cilia dysfunction", Hum Mol Genet, 26, 923-931 (2017)

  8. 8

    Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, Yanagawa Y, Tamamaki N, Hensch TK, Itohara S, and Yamakawa K: "Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome.", Hum Mol Genet, 22(23), 4784-4804 (2013)

  9. 9

    Ishihara K, Amano K, Takaki E, Shimohata A, Sago H, Epstein CJ, and Yamakawa K: "Enlarged brain ventricles and impaired neurogenesis in the Ts1Cje and Ts2Cje mouse models of Down syndrome.", Cereb Cortex, 20(5), 1131-43 (2010)

  10. 10

    Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T, Inoue Y, Kaneda M, and Yamakawa K.: "De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.", Neurology, 73(13), 1046-53 (2009)

  11. 11

    Suzuki T, Miyamoto H, Nakahari T, Inoue I, Suemoto T, Jiang B, Hirota Y, Itohara S, Saido TC, Tsumoto T, Sawamoto K, Hensch TK, Delgado-Escueta AV, and Yamakawa K: "Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility.", Hum Mol Genet, 18(6), 1099-109 (2009)

  12. 12

    Amano K, Fujii M, Arata S, Tojima T, Ogawa M, Morita N, Shimohata A, Furuichi T, Itohara S, Kamiguchi H, Korenberg JR, Arata A, and Yamakawa K: "DSCAM deficiency causes loss of pre-inspiratory neuron synchroneity and perinatal death.", J Neurosci, 29(9), 2984-96 (2009)

  13. 13

    Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, Takeuchi T, Itohara S, Yanagawa Y, Obata K, Furuichi T, Hensch TK, and Yamakawa K: "Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.", J Neurosci, 27(22), 5903-14 (2007)

  14. 14

    Shukkur EA, Shimohata A, Akagi T, Yu W, Yamaguchi M, Murayama M, Chui D, Takeuchi T, Amano K, Subramhanya KH, Hashikawa T, Sago H, Epstein CJ, Takashima A, and Yamakawa K: "Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome.", Hum Mol Genet, 15(18), 2752-62 (2006)

  15. 15

    Suzuki T, Delgado-Escueta AV, Aguan K, Alonso ME, Shi J, Hara Y, Nishida M, Numata T, Medina MT, Takeuchi T, Morita R, Bai D, Ganesh S, Sugimoto Y, Inazawa J, Bailey JN, Ochoa A, Jara-Prado A, Rasmussen A, Ramos-Peek J, Cordova S, Rubio-Donnadieu F, Inoue Y, Osawa M, Kaneko S, Oguni H, Mori Y, and Yamakawa K: "Mutations in EFHC1 cause juvenile myoclonic epilepsy.", Nat Genet, 36(8), 842-9 (2004)

  16. 16

    Amano K, Sago H, Uchikawa C, Suzuki T, Kotliarova SE, Nukina N, Epstein CJ, and Yamakawa K: "Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome.", Hum Mol Genet, 13(13), 1333-40 (2004)

  17. 17

    Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, Makita N, Tanaka M, Fukushima K, Fujiwara T, Inoue Y, and Yamakawa K: "A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline.", J Neurosci, 24(11), 2690-2698 (2004)

  18. 18

    Fujiwara T, Sugawara T, Mazaki-Miyazaki E, Takahashi Y, Fukushima K, Watanabe M, Hara K, Morikawa T, Yagi K, Yamakawa K*, and Inoue Y* (*co-corresponding authors): "Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.", Brain, 126(Pt 3), 531-46 (2003)

  19. 19

    Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai DS, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, and Yamakawa K: "Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice.", Hum Mol Genet, 11(11), 1251-62 (2002)

  20. 20

    Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, Nagafuji H, Noda M, Imoto K, Wada K, Mitsudome A, Kaneko S, Montal M, Nagata K, Hirose S, and Yamakawa K.: "A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.", Proc Natl Acad Sci U S A, 98(11), 6384-9 (2001)

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