Comprehensive genetic analysis of ALS-related genes in Japanese sporadic ALS patients

• Project/Area Number: 15K19485
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: NAKAMURA Ryoichi 名古屋大学, 医学部附属病院, 医員 (80723030)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 筋萎縮性側索硬化症 / ALS / 次世代シークエンサー / 網羅的遺伝子解析 / 遺伝子変異 / 分子疫学 / ターゲットリシークエンス / SOD1 / 網羅的解析 / ゲノム / 候補遺伝子 / 脳神経疾患

Outline of Final Research Achievements

To investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients, we designed a multiplex, PCR-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from Japanese sporadic ALS patients using an Ion Torrent PGM sequencer. We identified the known ALS pathogenic variants and predicted the functional properties of novel non-synonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored one or two novel non-synonymous variants of ALS-related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients.

Research Products

• [Journal Article] Involvement of the caudate nucleus head and its networks in sporadic amyotrophic (2017)
  • Author(s): Masuda, M., Senda, J., Watanabe, H., Epifanio, B., Tanaka, Y., Imai, K., Riku, Y., Li, Y., Nakamura, R., Ito, M., Ishigaki, S., Atsuta, N., Koike, H., Katsuno, M., Hattori, N., Naganawa, S., and Sobue, G.
  • Journal Title: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Volume: 17 Pages: 571-579
  • DOI: 10.1080/21678421.2016.1211151
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Structural MRI correlates of prognosis in amyotrophic lateral sclerosis (2017)
  • Author(s): Joe Senda、Naoki Atsuta、Hirohisa Watanabe、Bagarinao Epifanio Jr、Kazunori Imai、Daichi Yokoi、Yuchi Riku、Michihito Masuda、Ryoichi Nakamura、Hazuki Watanabe、Mizuki Ito、Masahisa Katsuno、Shinji Naganawa、Gen Sobue
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: in press
  • Peer Reviewed
• [Journal Article] Age of onset differentially influences the progression of regional dysfunction in sporadic amyotrophic lateral sclerosis (2016)
  • Author(s): Daichi Yokoi、Naoki Atsuta、Hazuki Watanabe、Ryoichi Nakamura、Akihiro Hirakawa、Mizuki Ito、Hirohisa Watanabe、Masahisa Katsuno、Yuishin Izumi、Mitsuya Morita、Akira Taniguchi、Masaya Oda、Koji Abe、Kouichi Mizoguchi、Osamu Kano、Satoshi Kuwabara、Ryuji Kaji、Gen Sobue、JaCALS
  • Journal Title: Journal of Neurology Volume: 263 Pages: 1129-1136
  • DOI: 10.1007/s00415-016-8109-0
  • Peer Reviewed
• [Journal Article] A rapid functional decline type of amyotrophic lateral sclerosis is linked to low (2016)
  • Author(s): Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Sobue G.
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: in press Pages: 851-8
  • DOI: 10.1136/jnnp-2015-311541
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS). Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort. (2016)
  • Author(s): Ryoichi Nakamura, Jun Sone, Naoki Atsuta, Genki Tohnai, Hazuki Watanabe, Daichi Yokoi, Masahiro Nakatochi, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe.
  • Journal Title: Neurobiol Aging. Volume: 39 Pages: 219-219
  • DOI: 10.1016/j.neurobiolaging.2015.11.030
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 孤発性筋萎縮性側索硬化症患者における発症年齢と遺伝学的背景に関する検討 (2016)
  • Author(s): 中村 亮一、曽根 淳、熱田 直樹、藤内 玄規、横井 大知、中杤 昌弘、渡辺 宏久、伊藤 瑞規、勝野 雅央、和泉 唯信、森田 光哉、谷口 彰、服部 信孝、織田 雅也、狩野 修、桑原 聡、阿部 康二、梶 龍兒、祖父江 元、JaCALS
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2016-05-18
• [Presentation] A rapid functional decline type of sporadic ALS is linked to low expression of TTN (2016)
  • Author(s): 渡辺 はづき、平川 晃弘、中村 亮一、中杤 昌弘、石垣 診祐、飯田 有俊、池川 志郎、横井 大知、勝野 雅央、和泉 唯信、森田 光哉、谷口 彰、阿部 康二、溝口 功一、狩野 修、梶 龍兒、祖父江 元、JaCALS
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2016-05-18
• [Presentation] The SMN gene copy number states in Japanese ALS patients (2016)
  • Author(s): 石原 智彦、豊田 佐織、小山 哲秀、熱田 直樹、中村 亮一、藤内 玄規、曽根 淳、和泉 唯信、梶 龍兒、森田 光哉、谷口 彰、祖父江 元、JaCALS、小野寺 理、西澤 正豊
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2016-05-18
• [Presentation] ALS患者に対する換気補助療法の予後 (2016)
  • Author(s): 横井 大知、熱田 直樹、渡辺 はづき、中村 亮一、平川 晃弘、伊藤 瑞規、渡辺 宏久、勝野 雅央、和泉 唯信、森田 光哉、谷口 彰、織田 雅也、阿部 康二、溝口 功一、狩野 修、桑原 聡、梶 龍兒、祖父江 元
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2016-05-18
• [Presentation] 次世代シークエンサーを用いたALS関連遺伝子多型の探索 (2016)
  • Author(s): 中村 亮一、祖父江 元、曽根 淳、中杤 昌弘、藤内 玄規、勝野 雅央、熱田 直樹.
  • Organizer: 平成27年度次世代シークエンサーを用いた孤発性の神経難病の発症機構の解明と治療法開発に関する研究班会議
  • Place of Presentation: 神戸大学医学部附属病院（兵庫県神戸市）
  • Year and Date: 2016-03-04
• [Presentation] Comprehensive genetic screening of 28 ALS-related genes in a Japanese ALS cohort (2015)
  • Author(s): Ryoichi Nakamura, Jun Sone, Naoki Atsuta, Genki Tohnai, Hazuki Watanabe, Daichi Yokoi, Masahiro Nakatochi, Hirohisa Watanabe, Mizuki Ito, Masahisa Katsuno, Fumiaki Tanaka, Nobutaka Hattori, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Koji Abe, Masaya Oda, Koichi Mizoguchi, Ryuji Kaji, Gen Sobue.
  • Organizer: 26th international symposium on ALS/MND
  • Place of Presentation: Orland (USA)
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] 日本におけるALS疾患関連遺伝子の網羅的解析 (2015)
  • Author(s): 中村亮一、曽根淳、熱田直樹、藤内玄規、中杤昌弘、渡辺はづき、横井大知、渡辺宏久、伊藤瑞規、勝野雅央、田中章景、服部信孝、和泉唯信、森田光哉、谷口彰、阿部康二、織田雅也、溝口功一、梶龍兒、祖父江元
  • Organizer: 第33回日本神経治療学会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋）
  • Year and Date: 2015-11-28