Elucidation of the Mechanism of Cardiac Pathology Caused by Mutations in the Splicing Regulator Rbm20

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08467
• 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: Tokyo Medical and Dental University
• Principal Investigator: Ihara Kensuke 東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (50770210)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: RBM20 / 選択的スプライシング / 拡張型心筋症 / 心房細動 / RNA代謝

Outline of Final Research Achievements

In this study, RNA immunoprecipitation and co-immunoprecipitation experiments were conducted on the mutant RBM20, revealing that the mutant RBM20 binds to RNA in the cytoplasm and interacts with proteins involved in RNA degradation. Additionally, when a mouse model specifically expressing the mutant RBM20 in the atria was created, it was found that the mutant RBM20 exhibited pathogenicity without affecting splicing functionality. This suggests that dilated cardiomyopathy caused by RBM20 mutations may contribute to the disease pathology through mechanisms different from the previously thought splicing regulation abnormalities, particularly implicating abnormalities in RNA metabolism due to the presence of mutant RBM20 in the cytoplasm.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究により変異型RBM20の不整脈原性への寄与が明らかとなり、また、変異型RBM20は細胞質においてP-bodyと相互作用を来しRNA代謝に影響を及ぼしている可能性が示唆された。変異型RBM20はRBM20変異による心病態において、新たな治療標的となりうることが示された。
また、近年RBM20遺伝子は一般人口においても心房細動発症に関与する遺伝子として報告されてきており、本研究結果は拡張型心筋症病態解明にとどまらず、脳梗塞の主要な原因となり社会的損失が大きく、やはり新たな治療法開発が望まれている心房細動に関しても全く新たな病態解明・治療法開発に波及効果をもたらす可能性が期待される。