Clarification of molecular mechanisms and establishment of appropriate therapies for atypical inherited arrhythmia syndromes

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09487
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Gunma University
• Principal Investigator: Nakajima Tadashi 群馬大学, 医学部附属病院, 講師 (40510574)
• Co-Investigator(Kenkyū-buntansha): 倉林 正彦 群馬大学, 大学院医学系研究科, 教授 (00215047) ; 金古 善明 群馬大学, 大学院医学系研究科, 准教授 (60302478)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 遺伝性不整脈 / 次世代シークエンス / イオンチャネル / 構造-機能連関 / 心脳チャネル病

Outline of Final Research Achievements

In patients with inherited arrhythmia syndromes (IASs) exhibiting unique or various phenotypes, optimal therapies have not been established. We sought to identify their responsible mutations using next generation sequencing (NGS), and reveal their pathophysiology using patch-clamp techniques.
1. We identified a novel RYR2 deletion in a family with atypical CPVT by focusing on read numbers of NGS, which help us provide an optimal therapy. 2. We revealed that SCN5A mutations (N1541D and R1632C) identified in patients with various phenotypes exhibited enhanced closed-state inactivation but through different mechanisms. 3. We encountered teenage siblings exhibiting both cardiac (ERS and PAF) and cerebral(epilepsy) phenotypes, in whom we identified a KCND3 V392I mutation with a mixed electrophysiological phenotype.
Our data will provide novel insights into structure-function relationships of ion channels, and lead to establish optimal therapies for IASs with unique or various phenotypes.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

我々は、病態が未解明で治療法も未確立の特異及び多彩な表現型を呈する遺伝性不整脈症候群において、遺伝子変異を同定し、さらに機能解析を行うことにより、病態を解明し得た。これらの研究成果は、臨床面では最適な治療法を確立し、さらに新規治療法の基礎を構築することにつながる可能性がある。一方、基礎研究面ではイオンチャネルの構造-機能連関に新たな知見をもたらすなど、多方面に派生する可能性がある。