Elucidation of the pathological mechanism of hereditary neuropathy based on novel causative genes discovered in Japan

• Project/Area Number: 20K16604
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kagoshima University
• Principal Investigator: Yujiro Higuchi 鹿児島大学, 医歯学域鹿児島大学病院, 助教 (10867724)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: シャルコー・マリー・トゥース病 / Charcot-Marie-Tooth病 / 遺伝性ニューロパチー / MME / ネプリライシン / COA7 / エクソーム解析 / 新規原因遺伝子 / Charcot-Marie- Tooth病

Outline of Research at the Start

遺伝性ニューロパチー(IPN)の代表であるCharcot-Marie-Tooth病(CMT)は末梢神経系が主に障害される遺伝性神経疾患である。申請者らの研究室は、2007年以降一貫して本邦のCMT遺伝子検査を継続し、多くの病型やCMT新規遺伝子を報告してきた。CMT/IPNは非常に多様であり、まだ未解明な部分が多く、有効な治療法も確立しておらず、病態解明および革新的な新薬の開発が急務である。本研究では、CMT遺伝子検査を継続しつつ、新規原因遺伝子を同定し、臨床・遺伝学・病理学的解析を行い、さらに病態モデル細胞・疾患モデル生物を樹立・解析することで、CMTの病態解明および治療法開発を目指す。

Outline of Final Research Achievements

We have continued genetic testing of 500 new CMT patients and reported the clinical and genetic characteristics of a cumulative total of 2598 CMT patients in our laboratory. We identified seven families with novel mutations in COA7, a novel causative gene we identified, and evaluated their phenotypes in detail. We revealed a wide variety of neurological signs, including neuropathy, cerebellar ataxia, extrapyramidal signs and spasticity. Regarding the new candidate gene "Gene X", we identified a total of five families and proceeded with phenotypic analysis, segregation analysis and functional analysis. The Drosophila knock down model of Gene X has been established and analyzed, and the pathogenetic mechanism has been elucidated. In addition, a knock-in mouse model has been established and phenotypic analysis is ongoing.

Academic Significance and Societal Importance of the Research Achievements

シャルコー・マリー・トゥース(CMT)病は末梢神経系が主に障害される遺伝性神経疾患である。本研究では、全国から依頼のあった新規のCMT患者500人の遺伝子検査を継続して実施し、これまでに解析した累計2598例の臨床的・遺伝学的特徴をまとめ学術論文として報告した。また、我々が同定した新規原因遺伝子であるMMEおよびCOA7変異を有する家系を多数同定し、表現型の多様性を明らかにした。さらに新規候補遺伝子については、計5家系を同定し、表現型の解析、家系分析データ、機能解析を進めた。本研究の成果は、本邦のCMT患者の遺伝子診断を確定し、CMTの病態解明や有効な治療法開発に寄与するものである。

Research Products

• [Journal Article] Clinical genetics of Charcot-Marie-Tooth disease (2022)
  • Author(s): Yujiro Higuchi and Hiroshi Takashima
  • Journal Title: Journal of Human Genetics Volume: - Issue: 3 Pages: 199-214
  • DOI: 10.1038/s10038-022-01031-2
  • Peer Reviewed
• [Journal Article] Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes (2022)
  • Author(s): Hiramatsu Yu、Okamoto Yuji、Yoshimura Akiko、Yuan Jun-Hui、Ando Masahiro、Higuchi Yujiro、Hashiguchi Akihiro、Matsuura Eiji、Takashima Hiroshi et al.
  • Journal Title: Journal of Neurology Volume: - Issue: 8 Pages: 4129-4140
  • DOI: 10.1007/s00415-022-11026-w
  • Peer Reviewed / Open Access
• [Journal Article] An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families (2022)
  • Author(s): Ando Masahiro、Higuchi Yujiro、Okamoto Yuji、Yuan Junhui、Yoshimura Akiko、Takei Jun、Taniguchi Takaki、Hiramatsu Yu、Sakiyama Yusuke、Hashiguchi Akihiro、Matsuura Eiji、Nakagawa Hiroto、Sonoda Ken、Yamashita Toru、Tamura Akiko、Terasawa Hideo、Mitsui Jun、Ishiura Hiroyuki、Tsuji Shoji、Takashima Hiroshi
  • Journal Title: Journal of Human Genetics Volume: - Issue: 7 Pages: 399-403
  • DOI: 10.1038/s10038-022-01019-y
  • Peer Reviewed
• [Journal Article] Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments (2022)
  • Author(s): Taniguchi Takaki、Ando Masahiro、Okamoto Yuji、Yoshimura Akiko、Higuchi Yujiro、Hashiguchi Akihiro、Matsuda Nozomu、Yamamoto Mamoru、Dohi Eisuke、Takahashi Makoto、Yoshino Masanao、Nomura Taichi、Matsushima Masaaki、Yabe Ichiro、Sanpei Yui、Ishiura Hiroyuki、Mitsui Jun、Nakagawa Masanori、Tsuji Shoji、Takashima Hiroshi
  • Journal Title: Journal of Human Genetics Volume: - Issue: 6 Pages: 353-362
  • DOI: 10.1038/s10038-021-01005-w
  • Peer Reviewed / Open Access
• [Journal Article] The first case of infantile-onset multisystem neurologic, endocrine, and pancreatic disease caused by novel PTRH2 mutation in Japan (2022)
  • Author(s): Ando Masahiro、Higuchi Yujiro、Takeuchi Mika、Hashiguchi Akihiro、Takashima Hiroshi
  • Journal Title: Neurological Sciences Volume: 43 Issue: 3 Pages: 2133-2136
  • DOI: 10.1007/s10072-021-05817-8
  • Peer Reviewed
• [Journal Article] Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan (2021)
  • Author(s): Higuchi Yujiro、Ando Masahiro、Yoshimura Akiko、Hakotani Satoshi、Koba Yuki、Sakiyama Yusuke、Hiramatsu Yu、Tashiro Yuichi、Maki Yoshimitsu、Hashiguchi Akihiro、Yuan Junhui、Okamoto Yuji、Matsuura Eiji、Takashima Hiroshi
  • Journal Title: The Cerebellum Volume: - Issue: 5 Pages: 851-860
  • DOI: 10.1007/s12311-021-01323-x
  • Peer Reviewed
• [Journal Article] Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan (2021)
  • Author(s): Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi, Kensuke Shiga, Arisa Hayashida, Taku Hatano, Hiroyuki Ishiura, Jun Mitsui, Nobutaka Hattori, Toshiki Mizuno, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima
  • Journal Title: Clinical Genetics Volume: 99 Issue: 3 Pages: 359-375
  • DOI: 10.1111/cge.13881
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of inherited neuropathy with BSCL2 mutations in Japan. (2020)
  • Author(s): Ishihara S, Okamoto Y, Tanabe H, Yoshimura A, Higuchi Y, Yuan JH, Hashiguchi A, Ishiura H, Mitsui J, Suwazono S, Oya Y, Sasaki M, Nakagawa M, Tsuji S, Ohya Y, Takashima H
  • Journal Title: J Peripher Nerv Syst Volume: - Issue: 2 Pages: 000-001
  • DOI: 10.1111/jns.12369
  • Peer Reviewed / Open Access
• [Journal Article] GARS変異による遺伝性末梢神経障害7例の臨床的特徴 (2020)
  • Author(s): 橋口昭大、吉村明子、安藤 匡宏、樋口雄二郎、中村友規、岡本裕嗣、松浦英治、髙嶋 博
  • Journal Title: 末梢神経 Volume: 31 Pages: 98-104
  • Peer Reviewed
• [Presentation] MME(ネプリライシン)遺伝子異常による常染色体劣性遺伝型CMTの臨床・遺伝学的検討 (2021)
  • Author(s): 樋口雄二郎
  • Organizer: 第32回日本末梢神経学会
• [Presentation] ニューロパチーの遺伝学 最新の知見（シンポジウム 日本初 遺伝性神経筋疾患 最新の発見） (2020)
  • Author(s): 樋口雄二郎
  • Organizer: 第61回日本神経学会学術大会
  • Invited