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Comprehensive whole genome sequence analysis using a long read sequencer for delineating molecular mechanism of neurological diseases

Research Project

Project/Area Number 17H05085
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionThe University of Tokyo

Principal Investigator

Ishiura Hiroyuki  東京大学, 医学部附属病院, 助教 (40632849)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥25,090,000 (Direct Cost: ¥19,300,000、Indirect Cost: ¥5,790,000)
Fiscal Year 2019: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2018: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Fiscal Year 2017: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Keywordsリピート伸長変異 / ロングリードシーケンサー / リピート伸長病 / ロングリード / 遺伝性神経疾患 / 良性成人型家族性ミオクローヌスてんかん / 次世代ゲノム解析 / 全ゲノム配列解析
Outline of Final Research Achievements

In benign adult familial myoclonic epilepsy (BAFME), expansions of intronic TTTCA and TTTTA repeats were identified in SAMD12, TNRC6A, and RAPGEF2. A new concept of repeat motif-phenotype correlation was proposed. The finding strongly indicates the gain-of-function of the expanded repeats is pathomechanism of BAFME.
The study also indicate the importance of genetic analysis focusing on repeat expansions. By applying this strategy to neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and oculopharyngodistal myopathy, CGG repeat expansions were identified in NOTCH2NLC, LOC642361/NUTM2B-AS1, LRP12, respectively.

Academic Significance and Societal Importance of the Research Achievements

良性成人型家族性ミオクローヌスてんかんの原因が、タンパク質に翻訳されない部分に存在するリピート伸長変異であることを発見した。また、3つの別個の遺伝子に存在するリピート伸長変異が同様の疾患を引き起こすという、てんかんにおける新しい機序を発見した。
同様の手法を応用し、神経核内封入体病、白質脳症を伴う眼咽頭型ミオパチー、眼咽頭遠位型ミオパチーについてもリピート伸長変異を新たに同定することに成功した。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (35 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (3 results) Journal Article (7 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 7 results,  Open Access: 1 results) Presentation (17 results) (of which Int'l Joint Research: 9 results,  Invited: 8 results) Remarks (5 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 2 results)

  • [Int'l Joint Research] University of Malaya(マレーシア)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Zhejiang University(中国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Zhejiang University(中国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Adult-onset Neuronal Intranuclear Inclusion Disease Mimicking Fragile X-associated Tremor-Ataxia Syndrome in Ethnic Chinese Patients2020

    • Author(s)
      Lim SY, Ishiura H, Ramli N, Shibata S, Almansour MA, Tan AH, Houlden H, Lang AE, Tsuji S.
    • Journal Title

      Parkinsonism Relat Disord.

      Volume: 74 Pages: 25-27

    • DOI

      10.1016/j.parkreldis.2020.03.025

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease2019

    • Author(s)
      Ishiura Hiroyuki、Shibata Shota、Yoshimura Jun、Suzuki YutaMano Tatsuo、Iwata Atsushi、Toda Tatsushi、Morishita Shinichi、Tsuji Shoji、et al
    • Journal Title

      Nature Genetics

      Volume: 51 Issue: 8 Pages: 1222-1232

    • DOI

      10.1038/s41588-019-0458-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.2019

    • Author(s)
      Florian RT, et al.
    • Journal Title

      Nat Commun

      Volume: 10 Issue: 1 Pages: 4919-4919

    • DOI

      10.1038/s41467-019-12763-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.2019

    • Author(s)
      Corbett MA, et al.
    • Journal Title

      Nat Commun

      Volume: 10 Issue: 1 Pages: 4920-4920

    • DOI

      10.1038/s41467-019-12671-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] An Autopsy Case of Familial Neuronal Intranuclear Inclusion Disease with Dementia and Neuropathy2018

    • Author(s)
      Yamaguchi Nanaka、Mano Tatsuo、Ohtomo Ryo、Ishiura Hiroyuki、Almansour M. Asem、Mori Harushi、Kanda Junko、Shirota Yuichiro、Taira Kenichiro、Morikawa Teppei、Ikemura Masako、Yanagi Yasuo、Murayama Shigeo、Shimizu Jun、Sakurai Yasuhisa、Tsuji Shoji、Iwata Atsushi
    • Journal Title

      Internal Medicine

      Volume: 57 Issue: 23 Pages: 3459-3462

    • DOI

      10.2169/internalmedicine.1141-18

    • NAID

      130007539687

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2018-12-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy2018

    • Author(s)
      Ishiura Hiroyuki、Doi Koichiro、Mitsui Jun、Yoshimura Jun、Matsukawa Miho Kawabe、Takahashi Yuji、Date Hidetoshi、Matsukawa Takashi、Shimizu Jun、Koh Kishin、Takiyama Yoshihisa、Goto Jun、Morishita Shinichi、Tsuji Shoji
    • Journal Title

      Nature Genetics

      Volume: 50 Issue: 4 Pages: 581-590

    • DOI

      10.1038/s41588-018-0067-2

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 12018

    • Author(s)
      Cen Zhidong、Jiang Zhengwen、Chen You、Zheng Xiaosheng、Xie Fei、Yang Xiaodong、Lu Xingjiao、Ouyang Zhiyuan、Wu Hongwei、Chen Si、Yin Houmin、Qiu Xia、Wang Shuang、Ding Meiping、Tang Yelei、Yu Feng、Li Caihua、Wang Tao、Ishiura Hiroyuki、Tsuji Shoji、Jiao Chuan、Liu Chunyu、Xiao Jianfeng、Luo Wei
    • Journal Title

      Brain

      Volume: 141 Issue: 8 Pages: 2280-2288

    • DOI

      10.1093/brain/awy160

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Noncoding CGG repeat expansions as common causative mutations for three diseases, neuronal intranuclear inclusion disease, oculophryngodistal myopathy, and an overlapping disease2019

    • Author(s)
      Ishiura H, et al.
    • Organizer
      American Society of Human Genetics 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Repeat configurations of CGG repeats in the NBPF19, a causative gene for neuronal intranuclear inclusion disease, and correlation of expanded CGG repeat sizes with age of onset2019

    • Author(s)
      Shibata S, et al.
    • Organizer
      American Society of Human Genetics 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Noncoding repeat expansions in epilepsy2019

    • Author(s)
      Ishiura H
    • Organizer
      13th Biennial Convention of the ASEAN Neurological Association
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular pathogenesis of benign adult familial myoclonic epilepsy (BAFME)2019

    • Author(s)
      Ishiura H
    • Organizer
      日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ロングリードシーケンサーを用いた遺伝性疾患の原因遺伝子の解明2018

    • Author(s)
      石浦 浩之
    • Organizer
      ゲノムテクノロジー第164委員会 第56回研究会「ロングリード・シーケンシングの医学応用・技術展望・情報解析」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 良性成人型家族性ミオクローヌスてんかんの分子遺伝学的研究2018

    • Author(s)
      石浦 浩之
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Pentanucleotide repeat expansion mutations in benign adult familial myoclonic epilepsy2018

    • Author(s)
      石浦 浩之
    • Organizer
      19th International Congress of Neuropathology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Expansions of intronic TTTCA and TTTTA repeats in three genes cause benign adult familial myoclonic epilepsy2018

    • Author(s)
      Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Kakita A, Qu W, Ichikawa K, Shibata S, Mitsue A, Ichikawa Y, Takahashi Y, Abe K, Koike R, Yasuda T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S.
    • Organizer
      American Society of Human Genetics 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy2018

    • Author(s)
      Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Kakita A, Qu W, Ichikawa K, Shibata S, Mitsue A, Abe K, Koike R, Yasuda T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S.
    • Organizer
      5th RNA metabolism in Neurological Disease Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] New genetics of myoclonus epilepsy2018

    • Author(s)
      Ishiura H.
    • Organizer
      Joint MSN-JSN symposium
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Genetics of spastic paraplegia: lessons from Japanese families2018

    • Author(s)
      Ishiura H.
    • Organizer
      Joint MSN-JSN symposium
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Genetics of non-coding repeat expansion diseases.2018

    • Author(s)
      Ishiura H.
    • Organizer
      2018 NTU-U Tokyo Joint Conference
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Genetic anticipation and clinical features of 32 patients with Benign Adult Familial Myoclonic Epilepsy (BAFME).2017

    • Author(s)
      Matsukawa M et al.
    • Organizer
      The XXIII World Congress of Neurology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Linkage and haplotype analyses of families with benign adult familial myoclonic epilepsy.2017

    • Author(s)
      Ishiura H et al.
    • Organizer
      The XXIII World Congress of Neurology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genetic anticipation of 32 patients with benign adult familial myoclonic epilepsy (BAFME)2017

    • Author(s)
      Matsukawa M et al.
    • Organizer
      日本人類遺伝学会第62回大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Linkage analysis of benign adult familial myoclonic epilepsy (BAFME) families suggests further genetic heterogeneity2017

    • Author(s)
      Ishiura H et al.
    • Organizer
      日本人類遺伝学会第62回大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Linkage and haplotype analyses of families with benign adult familial myoclonic epilepsy (BAFME)2017

    • Author(s)
      Ishiura H et al.
    • Organizer
      American Society of Human Genetics 2017 Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 別々の 3 疾患に共通する原因がヒトゲノム CGG 塩基の 繰り返し配列の異常伸長であることを解明

    • URL

      https://www.h.u-tokyo.ac.jp/press/__icsFiles/afieldfile/2019/07/25/release_20190723.pdf

    • Related Report
      2019 Annual Research Report
  • [Remarks] てんかんの新しい発症機構の解明―繰り返し配列の異常伸長によっててんかんが生じることを発見―

    • URL

      https://www.amed.go.jp/news/release_20180306-04.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] てんかんに認められたイントロンにおけるリピートの伸長変異

    • URL

      http://first.lifesciencedb.jp/archives/18095

    • Related Report
      2018 Annual Research Report
  • [Remarks] てんかんの新しい発症機構の解明 ―繰り返し配列の異常伸長によっててんかんが生じることを発見―

    • URL

      http://www.h.u-tokyo.ac.jp/vcms_lf/release_20180306.pdf

    • Related Report
      2018 Annual Research Report
  • [Remarks] てんかんの新しい発症機構の解明 ―繰り返し配列の異常伸長によっててんかんが生じることを発見―

    • URL

      http://www.h.u-tokyo.ac.jp/press/press_archives/20180306.html

    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] Detection of noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease2019

    • Inventor(s)
      Ishiura H, Tsuji S
    • Industrial Property Rights Holder
      Ishiura H, Tsuji S
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] DIAGNOSTIC METHOD OF BENIGN ADULT TYPE FAMILIAL MYOCLONUS EPILEPSY2018

    • Inventor(s)
      石浦浩之、辻省次
    • Industrial Property Rights Holder
      石浦浩之、辻省次
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] DIAGNOSTIC METHOD OF BENIGN ADULT TYPE FAMILIAL MYOCLONUS EPILEPSY2018

    • Inventor(s)
      石浦浩之、辻省次
    • Industrial Property Rights Holder
      石浦浩之、辻省次
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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