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

• Project/Area Number: 17H05085
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: The 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: ¥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。

Research Products

• [Int'l Joint Research] University of Malaya(マレーシア)
• [Int'l Joint Research] Zhejiang University(中国)
• [Int'l Joint Research] Zhejiang University(中国)
• [Journal Article] Adult-onset Neuronal Intranuclear Inclusion Disease Mimicking Fragile X-associated Tremor-Ataxia Syndrome in Ethnic Chinese Patients (2020)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease (2019)
  • 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
  • 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
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An Autopsy Case of Familial Neuronal Intranuclear Inclusion Disease with Dementia and Neuropathy (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy (2018)
  • 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
  • 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 1 (2018)
  • 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
  • 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 disease (2019)
  • Author(s): Ishiura H, et al.
  • Organizer: American Society of Human Genetics 2019
  • 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 onset (2019)
  • Author(s): Shibata S, et al.
  • Organizer: American Society of Human Genetics 2019
  • Int'l Joint Research
• [Presentation] Noncoding repeat expansions in epilepsy (2019)
  • Author(s): Ishiura H
  • Organizer: 13th Biennial Convention of the ASEAN Neurological Association
  • 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
  • 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」
  • 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
  • Invited
• [Presentation] Pentanucleotide repeat expansion mutations in benign adult familial myoclonic epilepsy (2018)
  • Author(s): 石浦 浩之
  • Organizer: 19th International Congress of Neuropathology
  • Int'l Joint Research / Invited
• [Presentation] Expansions of intronic TTTCA and TTTTA repeats in three genes cause benign adult familial myoclonic epilepsy (2018)
  • 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
  • Int'l Joint Research
• [Presentation] Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy (2018)
  • 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
  • Int'l Joint Research
• [Presentation] New genetics of myoclonus epilepsy (2018)
  • Author(s): Ishiura H.
  • Organizer: Joint MSN-JSN symposium
  • Invited
• [Presentation] Genetics of spastic paraplegia: lessons from Japanese families (2018)
  • Author(s): Ishiura H.
  • Organizer: Joint MSN-JSN symposium
  • Invited
• [Presentation] Genetics of non-coding repeat expansion diseases. (2018)
  • Author(s): Ishiura H.
  • Organizer: 2018 NTU-U Tokyo Joint Conference
  • 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
  • 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
  • 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
• [Presentation] Linkage analysis of benign adult familial myoclonic epilepsy (BAFME) families suggests further genetic heterogeneity (2017)
  • Author(s): Ishiura H et al.
  • Organizer: 日本人類遺伝学会第62回大会
• [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
  • 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
• [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
• [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
• [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
• [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
• [Patent(Industrial Property Rights)] Detection of noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease (2019)
  • Inventor(s): Ishiura H, Tsuji S
  • Industrial Property Rights Holder: Ishiura H, Tsuji S
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] DIAGNOSTIC METHOD OF BENIGN ADULT TYPE FAMILIAL MYOCLONUS EPILEPSY (2018)
  • 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
  • Overseas
• [Patent(Industrial Property Rights)] DIAGNOSTIC METHOD OF BENIGN ADULT TYPE FAMILIAL MYOCLONUS EPILEPSY (2018)
  • 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