Genetic and pathophysiological analysis of periodic paralyses

• Project/Area Number: 15K09314
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: Takahashi Masanori 大阪大学, 医学系研究科, 教授 (20359847)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: イオンチャネル / 骨格筋 / 心臓 / 次世代シークエンサ / 一塩基多型 / 電気生理 / パッチクランプ / 遺伝学的解析 / 反復発作性失調症 / 筋疾患

Outline of Final Research Achievements

Among skeletal muscle channelopathies, genetic and pathophysiological analyses were conducted, focusing on periodic paralysis of which pathomechanism is most poorly understood. Analysis of single nucleotide polymorphism was performed on sporadic periodic paralysis, which was not considered as hereditary due to a lack of family history, and clarified the existence of genetic background. We also found a case with multiple mutations suspected of pathogenicity and revealed that functional abnormalities due to both mutations contribute to disease severity. Similar cases are likely to be found more and more in the future due to the spread of next generation sequencing. Thus our finding, phenotypic modification by rare variant, is an important new pathological mechanism of channel disease.

Research Products

• [Int'l Joint Research] シカゴ大学(米国)
• [Int'l Joint Research] ICM ソルボンヌ大/IGBMC(フランス)
• [Int'l Joint Research] ICM、ソルボンヌ大学/IGBMC(フランス)
• [Int'l Joint Research] ストラスブール大学/ソルボンヌ大学(フランス)
• [Int'l Joint Research] フロリダ大学/マサチューセッツ工科大学(米国)
• [Int'l Joint Research] イエナ大学(ドイツ)
• [Journal Article] A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes. (2016)
  • Author(s): Kato H, Kokunai Y, Dalle C, Kubota T, Madokoro Y, Yuasa H, Uchida Y, Ikeda T, Mochizuki H, Nicole S, Fontaine B, Takahashi MP, Mitake S
  • Journal Title: J Neurol Sci Volume: 369 Pages: 254-258
  • DOI: 10.1016/j.jns.2016.08.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. (2016)
  • Author(s): Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y,.......Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 11067-11067
  • DOI: 10.1038/ncomms11067
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Episodic ataxia type 2 manifests as epileptiform electroencephalographic activity with no epileptic attacks in two family members (2016)
  • Author(s): 階堂三砂子, 古田 充, 中森雅之, 湯浅義人, 高橋正紀
  • Journal Title: Rinsho Shinkeigaku Volume: 56 Issue: 4 Pages: 260-264
  • DOI: 10.5692/clinicalneurol.cn-000854
  • NAID: 130005149743
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] Phenotypic variability in childhood of skeletal muscle sodium channelopathies. (2015)
  • Author(s): Yoshinaga H, Sakoda S, Shibata T, Akiyama T, Oka M, Yuan JH, Takashima H, Takahashi MP, Kitamura T, Murakami N, Kobayashi K.
  • Journal Title: Pediatr Neurol. Volume: 52 Issue: 5 Pages: 504-508
  • DOI: 10.1016/j.pediatrneurol.2015.01.014
  • Peer Reviewed
• [Presentation] Hypokalemic periodic paralysis cases with substitutions from arginine to lysine in the voltage sensor. (2018)
  • Author(s): Maki Nakaza, Tomoya Kubota, Savine Vicart, Daisuke Watanabe, Norito Kokubun, Mitsuru Furuta, Damien Sternberg, Yosuke Kokunai, Tatsuya Abe, Bertrand Fontaine, Masanori P. Takahashi
  • Organizer: 62nd Annual Meeting, Biophysical Society
  • Int'l Joint Research
• [Presentation] 遺伝性低カリウム性周期性四肢麻痺の発症機序とチャネル内電位感受性ドメインの電荷との関連について (2017)
  • Author(s): 久保田智哉、渡辺大祐、國分則人、古田充、穀内洋介、阿部達哉、高橋正紀
  • Organizer: 第3回日本筋学会学術集会
• [Presentation] rginine-to-lysine mutations in the voltage sensor are associated with hypokalemic periodic paralysis (2017)
  • Author(s): Kubota T, Watanabe D, Kokubun N, Furuta M, Kokunai Y, Abe T, Takahashi M.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 日本人コホートにおける孤発性周期性四肢麻痺の遺伝的背景 (2017)
  • Author(s): 高橋正紀 、仲座真希、北村友梨、古田 充、久保田智哉、佐々木良元
  • Organizer: 日本人類遺伝学会 第62回大会
• [Presentation] Naチャネルのスプライシング異常が筋強直性ジストロフィーの心臓伝導障害の原因となる (2016)
  • Author(s): 穀内洋介、Fernande Freyermuth 芦原貴司 伊藤英樹、紀嘉浩、中森雅之、木村卓、松村剛、藤村晴俊、望月秀樹、石浦章一、Swanson Maurice、堀江稔、Denis Furling Charlet-Berguerand Nicolas、高橋正紀
  • Organizer: 第2回日本筋学会学術集会
  • Place of Presentation: 東京（国立精神・神経医療研究センター）
• [Presentation] 格筋チャネル病の電気生理学的分類の限界について (2015)
  • Author(s): 高橋正紀、佐々木良元、久保田智哉、古田充、中森雅之、加藤秀紀、阿部達哉、國分則人、望月秀樹
  • Organizer: 第４５回日本臨床神経生理学会学術大会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-11-06
• [Presentation] 筋チャネル病‐周期性四肢麻痺および非ジストロフィー性ミオトニー症候群の遺伝子解析と麻痺発作重症度分類 (2015)
  • Author(s): 高橋正紀、佐々木良元、久保田智哉、穀内洋介、古田充、中森雅之、望月秀樹、冨本秀和、大野欽司
  • Organizer: 第1回日本筋学会学術集会
  • Place of Presentation: 国立精神・神経医療研究センター（小平市、東京）
  • Year and Date: 2015-08-07
• [Presentation] 著明な脳波異常を伴う反復発作性運動失調症２型（EA2）の一家系 (2015)
  • Author(s): 階堂三砂子、古田 充、中森雅之、湯浅義人、高橋正紀
  • Organizer: 日本神経学会第102回近畿地方会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-07-04
• [Book] 周期性失調症 神経疾患最新の治療2018-2020 (2018)
  • Author(s): 水澤 英洋、山口 修平、園生 雅弘
  • Total Pages: 370
  • Publisher: 南江堂
  • ISBN: 9784524252190
• [Remarks] 大阪大学大学院医学系研究科 保健学専攻 機能診断科学講座 臨床神経生理学
  • URL: http://sahswww.med.osaka-u.ac.jp/~neurolog/
• [Remarks] 大阪大学大学院医学系研究科保健学専攻機能診断科学講座臨床神経生理学
  • URL: http://sahswww.med.osaka-u.ac.jp/~neurolog/