パーソナルゲノム解析によるてんかんの分子生物学的発症機序の解明

2014 Fiscal Year Annual Research Report

• Project Area: Personal genome-based initiatives toward understanding bran diseases
• Project/Area Number: 25129708
• Research Institution: Fukuoka University
• Principal Investigator: 廣瀬 伸一 福岡大学, 医学部, 教授 (60248515)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: てんかん / 遺伝子変異 / エクソーム / 次世代シークエンサー

Outline of Annual Research Achievements

本研究は永らく不明である小児特発性てんかんの責任遺伝子の多くを網羅的に探索し、てんかんに対して遺伝子プロファイリングからのアプローチを用いて分子病態を解明することを目的とした。てんかん責任遺伝子の同定に次シークエンサーを用いた全エクソーム解析を実施した。はじめに、乳児悪性焦点移動性部分発作（MMPSI）と良性家族性新生児てんかん(BFNE）対象とした。独自の責任遺伝同定パイプラインとコンピュータープログラムを用いることにより責任遺伝子を絞り込んだ。MMPSI では19 のバリアントを絞り込んだ。現在確認をサンガー法で行っており、11 は偽陽性あることを確認して、残り8 個の中より原因遺伝子を確認中である。BFNE では、てんかん発作に係る824 遺伝子中に43 バリアントが存在した。この中であるK+チャネルの遺伝子のバリアントは発端者4 人中2 名共通していた。このチャネルはてんかんと関係すると報告されているKCNQ2、KCNQ3、KCNB1, KCNC1 のK+チャネルと密接な関係があった。このため変異を有する本K+チャネルの機能を解析中である。このほか、夜間前頭葉てんかんの9例に対しエクソームシークエンスを終了した。片麻痺性片頭痛に対しても4例で、PCDH19関連てんかんでは3家系の3トリオでのエクソームシークエンスを実施中である。熱性けいれんでは典型的な熱性けいれんの10家系10名でエクソームシークエンスを実施した。このように症例の集積により、原因遺伝子探索を引き続き行う予定である。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Single Nucleotide Variations in CLCN6 Identified in Patients with Benign Partial Epilepsies in Infancy and/or Febrile Seizures. (2015)
  • Author(s): Yamamoto T, Shimojima K, Sangu N, Komoike Y, Ishii A, Abe S, Yamashita S, Imai K, Kubota T, Fukasawa T, Okanishi T, Enoki H, Tanabe T, Saito A, Furukawa T, Shimizu T, Milligan CJ, Petrou S, Heron SE, Dibbens LM, Hirose S, Okumura A.
  • Journal Title: PLoS ONE Volume: 10(3) Pages: e0118946
  • DOI: 10.1371/journal.pone.0118946.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A case of recurrent encephalopathy with SCN2A missense mutation. (2015)
  • Author(s): Fukasawa T, Kubota T, Negoro T, Saitoh M, Mizuguchi M, Ihara Y, Ishii A, Hirose S.
  • Journal Title: Brain Dev Volume: 37(6) Pages: 631-4
  • DOI: 10.1016/j.braindev.2014.10.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] JNK is critical for the development of Candida albicans-induced vascular lesions in a mouse model of Kawasaki disease. (2015)
  • Author(s): Yoshikane Y, Koga M, Imanaka-Yoshida K, Cho T, Yamamoto Y, Yoshida T, Hashimoto J, Hirose S, Yoshimura K.
  • Journal Title: Cardiovasc Pathol. Volume: 24(1) Pages: 33-40
  • DOI: 10.1016/j.carpath.2014.08.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Trans-Golgi protein p230/golgin-245 is involved in phagophore formation. (2015)
  • Author(s): Sohda M, Misumi Y, Ogata S, Sakisaka S, Hirose S, Ikehara Y, Oda K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 456(1) Pages: 275-81
  • DOI: 10.1016/j.bbrc.2014.11.071.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical and genetic features of acute encephalopathy in children taking theophylline. (2015)
  • Author(s): Saitoh M, Shinohara M, Ishii A, Ihara Y, Hirose S, Shiomi M, Kawawaki H, Kubota M, Yamagata T, Miyamoto A, Yamanaka G, Amemiya K, Kikuchi K, Kamei A, Akasaka M, Anzai Y, Mizuguchi M.
  • Journal Title: Brain Dev Volume: 37 Pages: 463-70
  • DOI: 10.1016/j.braindev.2014.07.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of CYP2C19 polymorphisms on stiripentol administration in Japanese cases of Dravet syndrome. (2015)
  • Author(s): Kouga T, Shimbo H, Iai M, Yamashita S, Ishii A, Ihara Y, Hirose S, Yamakawa K, Osaka H.
  • Journal Title: Brain Dev Volume: 37(2) Pages: 243-9
  • DOI: 10.1016/j.braindev.2014.04.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy. (2015)
  • Author(s): Higurashi N, Takahashi Y, Kashimada A, Sugawara Y, Sakuma H, Tomonoh Y, Inoue T, Hoshina M, Satomi R, Ohfu M, Itomi K, Takano K, Kirino T, Hirose S.
  • Journal Title: Seizure Volume: 27 Pages: 1-5
  • DOI: 10.1016/j.seizure.2015.02.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The kick-in system: a novel rapid knock-in strategy. (2014)
  • Author(s): Tomonoh Y, Deshimaru M, Araki K, Miyazaki Y, Arasaki T, Tanaka Y, Kitamura H, Mori F, Wakabayashi K, Yamashita S, Saito R, Itoh M, Uchida T, Yamada J, Migita K, Ueno S, Kitaura H, Kakita A, Lossin C, Takano Y, Hirose S.
  • Journal Title: PLoS ONE Volume: 9(2) Pages: e88549
  • DOI: 10.1371/journal.pone.0088549
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures. (2014)
  • Author(s): Tomioka NH, Yasuda H, Miyamoto H, Hatayama M, Morimura N, Matsumoto Y, Suzuki T, Odagawa M, Odaka YS, Iwayama Y, Won Um J, Ko J, Inoue Y, Kaneko S, Hirose S, Yamada K, Yoshikawa T, Yamakawa K, Aruga J.
  • Journal Title: Nat Commun Volume: 5 Pages: 4501
  • DOI: 10.1038/ncomms5501
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genotype-phenotype correlations in alternating hemiplegia of childhood. (2014)
  • Author(s): Sasaki M, Ishii A, Saito Y, Morisada N, Iijima K, Takada S, Araki A, Tanabe Y, Arai H, Yamashita S, ｅｔ al 34番目
  • Journal Title: Neurology Volume: 82(6) Pages: 482-90
  • DOI: 10.1212/WNL.0000000000000102
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intermediate form between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism. (2014)
  • Author(s): Sasaki M, Ishii A, Saito Y, Hirose S.
  • Journal Title: Mov Disord Volume: 29(1) Pages: 153-4
  • DOI: 10.1002/mds.25659
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Exacerbation of benign familial neonatal epilepsy induced by massive doses of phenobarbital and midazolam. (2014)
  • Author(s): Maeda T, Shimizu M, Sekiguchi K, Ishii A, Ihara Y, Hirose S, Izumi T.
  • Journal Title: Pediatr Neurol Volume: 51(2) Pages: 259-61
  • DOI: 10.1016/j.pediatrneurol.2014.04.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Obesity attenuates D2 autoreceptor-mediated inhibition of putative ventral tegmental area dopaminergic neurons. (2014)
  • Author(s): Koyama S, Mori M, Kanamaru S, Sazawa T, Miyazaki A, Terai H, Hirose S.
  • Journal Title: Physiol Rep Volume: 2(5) Pages: e12004
  • DOI: 10.14814/phy2.12004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel SCN1A mutation in a cytoplasmic loop in intractable juvenile myoclonic epilepsy without febrile seizures. (2014)
  • Author(s): Jingami N, Matsumoto R, Ito H, Ishii A, Ihara Y, Hirose S, Ikeda A, Takahashi R.
  • Journal Title: Epileptic Disord Volume: 16(2) Pages: 227-31
  • DOI: 10.1684/epd.2014.0657
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy. (2014)
  • Author(s): Ishii A, Kanaumi T, Sohda M, Misumi Y, Zhang B, Kakinuma N, Haga Y, Watanabe K, Takeda S, Okada M, Ueno S, Kaneko S, Takashima S, Hirose S.
  • Journal Title: Epilepsy Res Volume: 108(3) Pages: 420-32
  • DOI: 10.1016/j.eplepsyres.2013.12.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy. (2014)
  • Author(s): Inoue T, Ihara Y, Tomonoh Y, Nakamura N, Ninomiya S, Fujita T, Ideguchi H, Yasumoto S, Zhang B, Hirose S.
  • Journal Title: Brain Dev Volume: 36(7) Pages: 613-9
  • DOI: 10.1016/j.braindev.2013.08.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Case of Desbuquois dysplasia type 1: potentially lethal skeletal dysplasia. (2014)
  • Author(s): Inoue S, Ishii A, Shirotani G, Tsutsumi M, Ohta E, Nakamura M, Mori T, Inoue T, Nishimura G, Ogawa A, Hirose S.
  • Journal Title: Pediatr Int Volume: 56(4) Pages: e26-9
  • DOI: 10.1111/ped.12383
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Distinct neurological disorders with ATP1A3 mutations. (2014)
  • Author(s): Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Johannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B, for the ATPAWG, (Hirose S, et al, ).
  • Journal Title: Lancet Neurol Volume: 13(5) Pages: 503-14
  • DOI: 10.1016/S1474-4422(14)70011-0
  • Open Access / Acknowledgement Compliant
• [Presentation] てんかんとiPS細胞 (2014)
  • Author(s): 廣瀨伸一
  • Organizer: 第44回日本臨床神経生理学会
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-19 – 2014-11-21
• [Presentation] A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy (2014)
  • Author(s): Okumura A, Ishii A, Shioda M, Kidokoro H, Sakauchi, M, Shimada S, Shimizu T, Osawa M, Hirose S, Yamamaoto T.
  • Organizer: The 16th annual meeting of the infantile seizure society
  • Place of Presentation: TURKEY
  • Year and Date: 2014-06-22 – 2014-06-27
• [Presentation] A Neonatal Case of Malignant Migrating Partial Seizures in infancy (2014)
  • Author(s): Sato T, Watanabe Y, Watanabe K, Yamashita M, Hashimoto K, Dateki S, Shirakawa T, Nakashima Y, Ihara Y, Ishii A, Hirose S, Moriuchi H
  • Organizer: The 16th annual meeting of the infantile seizure society
  • Place of Presentation: TURKEY
  • Year and Date: 2014-06-22 – 2014-06-27
• [Presentation] THE pathomechanisms of Dravet syndome:Lessons From patient-Derived Induced Pluripotent steｍ Cells(iPSCｓ） (2014)
  • Author(s): Hirose S
  • Organizer: The 16th annual meeting of the infantile seizure society
  • Place of Presentation: TURKEY
  • Year and Date: 2014-06-22 – 2014-06-27
  • Invited
• [Presentation] 最新技術でてんかんへ挑む (2014)
  • Author(s): 廣瀨伸一
  • Organizer: 第217回日本小児科学会宮城地方会
  • Place of Presentation: 宮城
  • Year and Date: 2014-06-08
• [Presentation] Newborn screening for Fabry disease:Prevalence and genotypes from a pilot study in Japan (2014)
  • Author(s): Inoue T, Hattori K, Ihara K, Ishii A, Nakamura K, Hirose S.
  • Organizer: The 2nd Asian Congress for Lysosomal Storage
  • Place of Presentation: 福岡
  • Year and Date: 2014-06-06
• [Book] Genetics of Epilepsy (2014)
  • Author(s): Hirose S
  • Total Pages: 31
  • Publisher: Prog Brain Res.
• [Book] 小児科研修ノート 第2版 (2014)
  • Author(s): 廣瀨 伸一
  • Total Pages: 3
  • Publisher: 診断と治療社