Elucidation of pathology of inherited cardiac disease caused by mutations in ryanodine receptor gene

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08555
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Fukuyama Megumi 滋賀医科大学, 医学部, 助教 (60625771)
• Co-Investigator(Kenkyū-buntansha): 大野 聖子 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025) ; 堀江 稔 滋賀医科大学, 医学部, 非常勤講師 (90183938)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: リアノジン受容体遺伝子異常 / QT延長症候群 / カテコラミン誘発多型性心室頻拍

Outline of Final Research Achievements

In a cohort of about 6,000 of inherited cardiac disease patients which we collected, we extracted 680 patients who were identified no mutation genes while exhibiting phenotypes of inherited cardiac disease, and screened for RYR2 gene variants. As the result, RYR2 variants were identified in 138 probands. As a result of analyzing the clinical and electrocardiographic characteristics in these RYR2 variant carriers, they were classified into 3 groups; 86 CPVT, 27 LQTS, and 8 IVF. 86% of them were symptomatic, overall, 52% of them experienced lethal arrhythmic events. These differences of phenotypes depend on protein function: gain-of-function in CPVT and loss-of-function in LQTS, and they seems to be related the position of variants in ryanodine receptor protein.

Free Research Field

遺伝性心臓疾患

Academic Significance and Societal Importance of the Research Achievements

リアノジン受容体は巨大蛋白であるため、心臓機能において重要な役割を果たすにもかかわらず遺伝子解析が煩雑なものであった。本研究ではRYR2遺伝子の大規模な解析により、本遺伝子異常がもたらす臨床像は致死的不整脈を含む重篤なものが多く、早期診断と初期からの治療介入の重要性を示すものであった。また、バリアントの部位や蛋白機能変化により臨床像が異なることを明らかにしたことで、バリアントから患者の表現型や不整脈リスクを予測することができ、治療や安全管理の上で非常に役立つと考えられる。