Diastolic dysfunction caused by titin mutation

2015 Fiscal Year Final Research Report

• Project/Area Number: 24390201
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Keio University
• Principal Investigator: Makino Shinji 慶應義塾大学, 医学部, 准教授 (20306707)
• Co-Investigator(Kenkyū-buntansha): YAMAGISHI TAKAYUKI 慶應義塾大学, 医学部, 准教授 (40255500) ; ARIMURA TAKURO 東京医科歯科大学, 難治疾患研究所, 助教 (50342887)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: 家族性心筋症 / 拡張不全 / メダカ変異体

Outline of Final Research Achievements

Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. We generated a cardiovascular-mutant medaka fish non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh had expressed pathologically stiffer titin isoforms. The nsh heterozygotes showed M-line disassembly. Positional cloning revealed a missense mutation in an immunoglobulin domain located in the M-line-A-band transition zone of titin. Screening of mutations in 96 unrelated　patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. The mutations found in both medaka fish and in familial HCM increased binding of titin to MURF1 and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.

Free Research Field

循環器内科