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Electrophysiological analysis of pathogenesis and effective therapy for early repolarization syndrome

Research Project

Project/Area Number 19K17593
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53020:Cardiology-related
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

Takayama Koichiro  国立研究開発法人国立循環器病研究センター, 研究所, 流動研究員 (20816988)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords早期再分極症候群 / KCND3変異 / 一過性外向きカリウム電流 / 機能獲得型障害 / キニジン / ベプリジル / 疾患モデルiPS細胞 / 若年性心臓突然死 / 心筋イオンチャネルの遺伝子変異
Outline of Research at the Start

早期再分極症候群(ERS)は若年性心臓突然死の原因となる悪性の疾患であり、比較的新しい疾患概念である。遺伝性があり、一部は遺伝子変異による心筋イオンチャネルの異常が原因と報告されているが、病因や病態は未だ解明されていない。
これまで原因不明の致死性不整脈と診断されていた患者群において、臨床情報を再評価して診断を改め、網羅的に心筋イオンチャネルなどの遺伝子異常を検索する。そして、同定された遺伝子異常が、心筋細胞においてどのような機能異常を引き起こすのか実験によって明らかにする。さらに、その機能異常を正常化させる効果的な治療薬を探索し、ERSの治療薬確立を目指す。

Outline of Final Research Achievements

Early repolarization syndrome (ERS) is one of the diseases which cause sudden cardiac death in young people. I detected a new KCND3 heterozygous mutation, p.Gly306Ala, in one of 11 ERS patients. In electrophysiological analysis using cultured cells expressing mutant Kv4.3 encoded by KCND3, I found that the mutation caused gain-of-function disorder of transient outward potassium current (Ito) produced by Kv4.3, and that quinidine and bepridil, which were Ito blockers, concentration-dependently restored the disorder. For the further experiment, I established a human iPS cell model of ERS with the KCND3 mutation by genome editing and succeeded in setting up an experimental system using cardiomyocytes differentiated from the iPS cells.

Academic Significance and Societal Importance of the Research Achievements

ERSは比較的新しい疾患概念のため未解明な部分が多い。本研究成果は、原因遺伝子の同定、電気生理学的な病態解明、薬の効果発現のメカニズム解明において貢献できた。今後は、KCND3遺伝子検査によって、原因不明の特発性心室細動患者の正確な診断が可能となり、キニジンなどの適切な薬剤を使用することで若年者心臓突然死を予防することができるだろう。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (2 results)

All 2019

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] A de novo gain-of-function KCND3 mutation in early repolarization syndrome2019

    • Author(s)
      Takayama Koichiro、Ohno Seiko、Ding Wei-Guang、Ashihara Takashi、Fukumoto Daisuke、Wada Yuko、Makiyama Takeru、Kise Hiroaki、Hoshiai Minako、Matsuura Hiroshi、Horie Minoru
    • Journal Title

      Heart Rhythm

      Volume: 16 Issue: 11 Pages: 1698-1706

    • DOI

      10.1016/j.hrthm.2019.05.033

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Low Dose of Quinidine is Effective to Normalize the Slow Inactivation in Mutant Kv4.3 Channel Identified in an Early Repolarization Syndrome Patient2019

    • Author(s)
      Koichiro Takayama, Wei-Guang Ding, Hiroshi Matsuura, Minoru Horie, Seiko Ohno
    • Organizer
      欧州心臓病学会(ESC)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2022-01-27  

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