Molecular pathogenesis of heart failure and arrhythmia caused by gene abnormalities

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05296
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KIMURA Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 遺伝学 / 遺伝子 / ゲノム / 循環器・高血圧 / 生体分子

Outline of Final Research Achievements

Targeted sequencing system for disease genes of hereditary cardiomyopathy and/or hereditary arrhythmia was developed. RBM20 mutations in dilated cardiomyopathy were demonstrated for functional alterations. A novel disease gene for hypertrophic cardiomyopathy was identified, which altered methylation status of several specific loci in genome DNA. Analysis of transgenic mice specifically expressing human M21 in the heart demonstrated that high expression of M21 lead to cardiomyocytes hypertrophy with myofibrillar disarrays and later development of systolic dysfunction resembling to dilated phase hypertrophic cardiomyopathy, while low expression of M21 did not. Gene expression study revealed that expression of cardiac remodeling genes were altered even in the hearts from mice with low expressing M21, while MAP kinase and TGFb pathways were specifically changed only in the hearts from mice with high expression of M21.

Free Research Field

人類遺伝学

Academic Significance and Societal Importance of the Research Achievements

本研究では、遺伝性心筋症・遺伝性不整脈について、既知の原因遺伝子の変異を網羅的に検索するシステムを構築し、その有用性を示した。また、新たに見出した多数の病因変異の機能異常を解明した。とりわけ、RBM20変異による拡張型心筋症の病態形成機序やカルシウム感受性異常が肥大型心筋症の病態形成に至る機序を解明した。さらに、新規の原因遺伝子を複数同定した。これらの知見は、遺伝性心疾患の診断や病態解明に供するのみならず、一般の心不全・不整脈の病態解明ひいては治療法開発にも繋がる。