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Elucidating molecular network of Dravet syndrome by genetic approaches

Research Project

Project/Area Number 19K17381
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionFukuoka International University of Health and Welfare (2022)
International University of Health and Welfare (2021)
Fukuoka University (2019-2020)

Principal Investigator

石井 敦士  福岡国際医療福祉大学, 医療学部, 教授 (90568825)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsてんかん / ドラべ症候群 / バリアント / ネットワーク / 遺伝子 / 次世代シークエンサー / ドラベ症候群 / エクソーム解析 / 遺伝子解析 / 発達性てんかん性脳症
Outline of Research at the Start

多彩な症状かつ難治性てんかんを特徴とするドラベ症候群の分子病態は依然として明確ではない。欧米では約70%に同定される電位依存性ナトリウムイオンチャネルをコードするSCN1A遺伝子変異を持つドラベ症候群でさえ、その多彩な症状を説明しうる理由は解明されておらず、変異を持たないドラベ症候群は更に謎である。多彩な症状の原因となる遺伝子を網羅し、その遺伝子異常による神経細胞内の他の分子発現量の影響を明らかにし、分子ネットワークの全容を捉えることに取り組む。

Outline of Annual Research Achievements

ドラベ症候群の分子ネットワークを明らかにすることを目的に、500症例の発達性てんかん性脳症症例を解析した。抹消リンパ球より抽出されたゲノムDNAを用いて、てんかん関連の114遺伝子のエクソンを含む領域にプローブを設計しライブラリを作成した。次世代シークエンサーMiseq(イルミナ社)でシークエンスを行い、fastq fileを参照ゲノム配列hg19を使用してバリアントを抽出したvcf fileを作成した。AnnotationはANNOVARを使用し、1000 genome, ExAC, gnomADデータベースで新規バリアントを抽出し、SIFT、 PolyPhen2、CADDスコアで有害性が予測されるバリアントを候補とした。候補バリアントに対して、両親のゲノムDNAでバリアントの有無をPCRサンガー法で確認し、新生バリアントを病的バリアントとした。Na+、K+、Cl-チャネル、GABAA受容体等のイオンチャネル、イオンチャネル内蔵をコードする遺伝子を対象とした。
ドラべ症候群337症例、その他の発達性てんかん性脳症163症例の合計500症例で病的バリアントを探索し、121症例(ドラべ症候群95症例、発達性てんかん性脳症26症例)に病的バリアントを同定した。トップ5の遺伝子は、SCN1Aに85症例、SCN8Aに7症例、KCNT1に5症例、KCNQ2に4症例、GABRB2に3症例であった。チャネル種類に分類すると。Na+チャネルに93症例、K+チャネルに12症例、GABAA受容体に7症例であった。
Na+チャネルが最も多いが、K+チャネル、GABAA受容体と抑制性のチャネルが続き、抑制性チャネルのバリアントの関与も示唆された。

Report

(4 results)
  • 2022 Annual Research Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (47 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (29 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 25 results,  Open Access: 10 results) Presentation (14 results) (of which Int'l Joint Research: 3 results,  Invited: 6 results) Remarks (1 results)

  • [Int'l Joint Research] Baylor College of Medicine(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Broad Institute of MIT and Harvard(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] University of Melbourne(オーストリア)

    • Related Report
      2020 Research-status Report
  • [Journal Article] The effectiveness of intravenous benzodiazepine for status epilepticus in Dravet syndrome.2022

    • Author(s)
      Kikuchi K, Hamano SI, Matsuura R, Nonoyama H, Daida A, Hirata Y, Koichihara R, Hirano D, Ishii A, Hirose S.
    • Journal Title

      Brain Dev

      Volume: 44(5) Issue: 5 Pages: 319-28

    • DOI

      10.1016/j.braindev.2022.01.004

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome2022

    • Author(s)
      Morishita Takashi、Sakai Yuki、Iida Hitoshi、Yoshimura Saki、Ishii Atsushi、Fujioka Shinsuke、Tanaka Saori C.、Inoue Tooru
    • Journal Title

      Journal of Neurosurgery

      Volume: 136 Issue: 1 Pages: 231-241

    • DOI

      10.3171/2021.2.jns204026

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate2022

    • Author(s)
      Suzuki T, Tatsukawa T, Sudo G, Delandre C, Pai YJ, Miyamoto H, Raveau M, Shimohata A, Ohmori I, Hamano S, Haginoya K, Uematsu M, Takahashi Y, Morimoto M, Fujimoto S, Osaka H, Oguni H, Osawa M, Ishii A, Hirose S, Kaneko S, Inoue Y, Moore AW, Yamakawa K.
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 6505-6505

    • DOI

      10.1038/s41598-022-10715-w

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Burden of seizures and comorbidities in patients with epilepsy: a survey based on the tertiary hospital-based Epilepsy Syndrome Registry in Japan.2022

    • Author(s)
      Inoue Y, Hamano SI, Hayashi M, Sakuma H, Hirose S, Ishii A, Honda R, Ikeda A, Imai K, Jin K, Kada A, Kakita A, Kato M, Kawai K, Kawakami T, Kobayashi K, Matsuishi T, Matsuo T, Nabatame S, Okamoto N, Ito S, Okumura A, Saito A, Shiraishi H, Shirozu H, Saito T, Sugano H, Takahashi Y, Yamamoto H, Fukuyama T, Kuki I.
    • Journal Title

      Epileptic Disord

      Volume: 24 Issue: 1 Pages: 82-94

    • DOI

      10.1684/epd.2021.1361

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutation in the STXBP1 Gene Associated with Early Onset West Syndrome: A Case Report and Literature Review2022

    • Author(s)
      Takeda Kanako、Miyamoto Yusaku、Yamamoto Hisako、Iwasaki Toshiyuki、Sumitomo Noriko、Takeshita Eri、Ishii Atsushi、Hirose Shinichi、Shimizu Naoki
    • Journal Title

      Pediatric Reports

      Volume: 14 Issue: 4 Pages: 386-395

    • DOI

      10.3390/pediatric14040046

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Precision medicine~遺伝子変異によるてんかんとその治療~2022

    • Author(s)
      石井敦士
    • Journal Title

      Epilepsy

      Volume: 16 Pages: 99-105

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 神経疾患と遺伝子検索2022

    • Author(s)
      石井敦士
    • Journal Title

      小児内科

      Volume: 54 Pages: 236-239

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 新生児けいれんを起こし, 遺伝子異常を認めた6症例の比較2022

    • Author(s)
      大滝里美, 颯佐かおり, 寺西宏美, 櫻井隼人, 國方徹也, 石井敦士, 加藤光広, 山内秀雄
    • Journal Title

      脳と発達 54(4): 290-290, 2022.

      Volume: 54 Pages: 290-290

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals2021

    • Author(s)
      Epi25 Collaborative
    • Journal Title

      The American Journal of Human Genetics

      Volume: 108 Issue: 6 Pages: 965-982

    • DOI

      10.1016/j.ajhg.2021.04.009

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Current medico-psycho-social conditions of patients with West syndrome in Japan2021

    • Author(s)
      Yoshitomi S, Hamano SI, Hayashi M, ... Matsuo T (18/32), et al
    • Journal Title

      Epileptic Disord

      Volume: 23 Issue: 4 Pages: 579-589

    • DOI

      10.1684/epd.2021.1301

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 10:遺伝子変異2020

    • Author(s)
      Ishii Atsushi
    • Journal Title

      Journal of the Japan Epilepsy Society

      Volume: 37 Issue: 3 Pages: 828-836

    • DOI

      10.3805/jjes.37.828

    • NAID

      130007792103

    • ISSN
      0912-0890, 1347-5509
    • Year and Date
      2020-01-31
    • Related Report
      2020 Research-status Report
  • [Journal Article] Comparative characterization of PCDH19 missense and truncating variants in PCDH19-related epilepsy2020

    • Author(s)
      Shibata Mami、Ishii Atsushi、Goto Ayako、Hirose Shinichi
    • Journal Title

      Journal of Human Genetics

      Volume: 66 Issue: 6 Pages: 569-578

    • DOI

      10.1038/s10038-020-00880-z

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical features of early myoclonic encephalopathy caused by a CDKL5 mutation.2020

    • Author(s)
      Takeda K, Miyamoto Y, Yamamoto H, Ishii A, Hirose S, Yamamoto H.
    • Journal Title

      Brain Dev.

      Volume: 42 Issue: 1 Pages: 73-76

    • DOI

      10.1016/j.braindev.2019.08.003

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Case-control association study of rare nonsynonymous variants of SCN1A and KCNQ2 in acute encephalopathy with biphasic seizures and late reduced diffusion2020

    • Author(s)
      Shibata Akiko、Kasai Mariko、Terashima Hiroshi、Hoshino Ai、Miyagawa Taku、Kikuchi Kenjiro、Ishii Atsushi、Matsumoto Hiroshi、Kubota Masaya、Hirose Shinichi、Oka Akira、Mizuguchi Masashi
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 414 Pages: 116808-116808

    • DOI

      10.1016/j.jns.2020.116808

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Application of induced pluripotent stem cells in epilepsy2020

    • Author(s)
      Hirose Shinichi、Tanaka Yasuyoshi、Shibata Mami、Kimura Yuichi、Ishikawa Mitsuru、Higurashi Norimichi、Yamamoto Toshiyuki、Ichise Eisuke、Chiyonobu Tomohiro、Ishii Atsushi
    • Journal Title

      Molecular and Cellular Neuroscience

      Volume: 108 Pages: 103535-103535

    • DOI

      10.1016/j.mcn.2020.103535

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coffin‐Siris syndrome with bilateral macular dysplasia caused by a novel exonic deletion in ARID1B2020

    • Author(s)
      Fujita Takako、Ihara Yukiko、Hayashi Hitomi、Ishii Atsushi、Ideguchi Hiroshi、Inoue Takahito、Imaizumi Taichi、Yamamoto Toshiyuki、Hirose Shinichi
    • Journal Title

      Congenital Anomalies

      Volume: 60 Issue: 6 Pages: 189-193

    • DOI

      10.1111/cga.12383

    • NAID

      50014626632

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epidemiological changes of acute encephalopathy in Japan based on national surveillance for 2014-20172020

    • Author(s)
      Kasai Mariko、Shibata Akiko、Hoshino Ai、Maegaki Yoshihiro、Yamanouchi Hideo、Takanashi Jun-ichi、Yamagata Takanori、Sakuma Hiroshi、Okumura Akihisa、Nagase Hiroaki、Ishii Atsushi、Goto Tomohide、Oka Akira、Mizuguchi Masashi
    • Journal Title

      Brain and Development

      Volume: ー Issue: 7 Pages: 508-514

    • DOI

      10.1016/j.braindev.2020.04.006

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glucose transporter type 1 deficiency syndrome associated with autoantibodies to glutamate receptors2020

    • Author(s)
      Hoshino Hiroki、Takayama Kazuko、Ishii Atsushi、Takahashi Yukitoshi、Kanemura Hideaki
    • Journal Title

      Brain and Development

      Volume: 42 Issue: 9 Pages: 686-690

    • DOI

      10.1016/j.braindev.2020.05.010

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Learning-1 てんかん2020

    • Author(s)
      Ishii Atsushi
    • Journal Title

      遺伝子医学

      Volume: 33

    • Related Report
      2020 Research-status Report
  • [Journal Article] 続編 てんかんを分かり易く理解するための神経科学 遺伝子変異2020

    • Author(s)
      石井 敦士
    • Journal Title

      てんかん研究

      Volume: 37 Pages: 828-836

    • Related Report
      2019 Research-status Report
  • [Journal Article] Heart rate variability in a patient with alternating hemiplegia2019

    • Author(s)
      Nakashima Tsutomu、Yasuda Kanji、Kobayashi Makoto、Wada Hisayasu、Ishii Atsushi、Hirose Shinichi
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 8 Issue: 2 Pages: 134-137

    • DOI

      10.5582/irdr.2019.01060

    • NAID

      130007663250

    • ISSN
      2186-361X, 2186-3644
    • Year and Date
      2019-05-31
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy2019

    • Author(s)
      Goto Ayako、Ishii Atsushi、Shibata Mami、Ihara Yukiko、Cooper Edward C.、Hirose Shinichi
    • Journal Title

      Epilepsia

      Volume: 60 Issue: 9 Pages: 1870-1880

    • DOI

      10.1111/epi.16314

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Copy number variation analysis in 83 children with early-onset developmental and epileptic encephalopathy after targeted resequencing of a 109-epilepsy gene panel2019

    • Author(s)
      Hirabayashi Kyoko、Uehara Daniela Tiaki、Abe Hidetoshi、Ishii Atsushi、Moriyama Keiji、Hirose Shinichi、Inazawa Johji
    • Journal Title

      Journal of Human Genetics

      Volume: 64 Issue: 11 Pages: 1097-1106

    • DOI

      10.1038/s10038-019-0661-x

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] PRRT2 mutations in Japanese patients with benign infantile epilepsy and paroxysmal kinesigenic dyskinesia2019

    • Author(s)
      Okumura Akihisa、Shimojima Keiko、Kurahashi Hirokazuら.
    • Journal Title

      Seizure

      Volume: 71 Pages: 1-5

    • DOI

      10.1016/j.seizure.2019.05.017

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Different types of suppression-burst patterns in patients with epilepsy of infancy with migrating focal seizures (EIMFS)2019

    • Author(s)
      Yoshitomi Shinsaku、Takahashi Yukitoshi、Imai Katsumi、Koshimizu Eriko、Miyatake Satoko、Nakashima Mitsuko、Saitsu Hirotomo、Matsumoto Naomichi、Kato Mitsuhiro、Fujita Takako、Ishii Atsushi、Hirose Shinichi、Inoue Yushi
    • Journal Title

      Seizure

      Volume: 65 Pages: 118-123

    • DOI

      10.1016/j.seizure.2019.01.009

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Corrigendum to “Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome” [Epilepsy Res. 154 (2019) 34?38]2019

    • Author(s)
      Yoshitomi Shinsaku、Takahashi Yukitoshi、Yamaguchi Tokito、Imai Katsumi、Ishii Atsushi、Hirose Shinichi、Inoue Yushi
    • Journal Title

      Epilepsy Research

      Volume: 156 Pages: 106158-106158

    • DOI

      10.1016/j.eplepsyres.2019.106158

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome2019

    • Author(s)
      Yoshitomi Shinsaku、Takahashi Yukitoshi、Yamaguchi Tokito、Imai Katsumi、Ishii Atsushi、Hirose Shinichi、Inoue Yushi
    • Journal Title

      Epilepsy Research

      Volume: 154 Pages: 34-38

    • DOI

      10.1016/j.eplepsyres.2019.02.014

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Quinidine therapy and therapeutic drug monitoring in four patients with KCNTI mutations.2019

    • Author(s)
      Yoshitomi S, Takahashi Y, Yamaguchi T, Oboshi T, Horino A, Ikeda H, Imai K, Okanishi T, Nakashima M, Saitsu H, Matsumoto N, Yoshimoto J, Fujita T, Ishii A, Hirose S, Inoue Y.
    • Journal Title

      Epileptic Disorders

      Volume: 21 Issue: 1 Pages: 48-54

    • DOI

      10.1684/epd.2019.1026

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] 【小児神経難病の臨床】Dravet症候群2019

    • Author(s)
      石井 敦士
    • Journal Title

      小児科

      Volume: 60 Pages: 941-947

    • Related Report
      2019 Research-status Report
  • [Presentation] Beyond genetic basis of monogenic developmental and epileptic encephalopathy2020

    • Author(s)
      Atsushi Ishii
    • Organizer
      The 21st Annual Meeting of Infantile Seizure Society, International Symposium on the Pathophysiology of Developmental and Epileptic Encephalopathy
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] てんかんの遺伝子研究と日常診療での役立ち2020

    • Author(s)
      石井 敦士
    • Organizer
      日本てんかん学会中国四国地方会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Dravet症候群における発熱時および平熱時の免疫学的反応の解析2019

    • Author(s)
      倉橋 宏和, 沼本 真吾, 奥村 彰久, 石井 敦士, 廣瀬 伸一
    • Organizer
      第53回日本てんかん学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 基礎研究からさぐるてんかん病態: 臨床に役立つ知見 てんかんの遺伝子研究2019

    • Author(s)
      石井 敦士
    • Organizer
      第53回日本てんかん学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] てんかんと遺伝子 てんかん遺伝子情報の解釈の問題点2019

    • Author(s)
      石井 敦士
    • Organizer
      第53回日本てんかん学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] カルバマゼピンによる治療が有効であったKCNQ2-related neonatal epilepsyの1例2019

    • Author(s)
      竹内 章人, 廣瀬 伸一, 森本 大作, 中村 信, 影山 操, 石井 敦士
    • Organizer
      第64回 日本新生児成育医学会・学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] KCNA2遺伝子変異に伴うてんかん性脳症の1男児例2019

    • Author(s)
      重田 英臣, 福田 智文, 柴原 淳平, 五十嵐 亮太, 石井 雅宏, 楠原 浩一, 石井 敦士, 廣瀬 伸一
    • Organizer
      第122回日本小児科学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 遊走性焦点発作を伴う乳児てんかんにおける発作抑制期間と発達予後の関連2019

    • Author(s)
      野村 敏大, 本橋 裕子, 石山 昭彦, 竹下 絵里, 齋藤 貴志, 小牧 宏文, 中川 栄二, 須貝 研司, 才津 浩智, 藤田 京志, 松本 直通, 石井 敦士, 廣瀬 伸一, 佐々木 征行
    • Organizer
      第61回日本小児神経学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] HCN1遺伝子バリアントの早期乳児てんかん性脳症の1例2019

    • Author(s)
      久保田 弘樹, 矢野 珠巨, 高橋 勉, 石井 敦士, 柴田 磨己, 廣瀬 伸一
    • Organizer
      第61回日本小児神経学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] PCDH19遺伝子関連てんかん3症例の臨床的特徴2019

    • Author(s)
      田辺 仁彦, 林田 拓也, 戸川 雅美, 西村 洋子, 三浦 明彦, 石井 敦士, 前垣 義弘
    • Organizer
      第61回日本小児神経学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Regional specificity of KCNQ2 missense variants causing benign or epileptic encephalopathy phenotype.2019

    • Author(s)
      Atsushi Ishii, Ayako Goto, Mami Shibata, Yukiko Ihara, Shinichi Hirose
    • Organizer
      33rd International Epilepsy Congress
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Genetic etiology of neonatal epilepsiesby causes other than abnormalities of sodium ion channels2019

    • Author(s)
      Atsushi Ishii
    • Organizer
      20th Annual Meeting of Infantile Seizure Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] てんかんの遺伝子研究の進歩2019

    • Author(s)
      石井 敦士
    • Organizer
      506回小児科学会福岡地方会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] てんかんのPrecision medicineの基盤となる遺伝子研究2019

    • Author(s)
      石井 敦士
    • Organizer
      第52回日本てんかん学会学術集会記念シンポジウム
    • Related Report
      2019 Research-status Report
    • Invited
  • [Remarks] SCN1A.NET

    • URL

      https://www.scn1a.net/

    • Related Report
      2021 Research-status Report 2020 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2025-11-20  

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