期刊
CIRCULATION-CARDIOVASCULAR GENETICS
卷 10, 期 6, 页码 -出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.117.001780
关键词
atrial fibrillation; cardiomyopathy; restrictive; mutation; stem cells; ventricular function
资金
- National Institutes of Health (NIH) [T32HL007208]
- Carol and Roch Hillenbrand and the George L. Nardi, MD, Memorial Research Fund
- European Community [PIOF-GA-2012-328352]
- German Centre for Cardiovascular Research
- NIH [1RO1HL092577, R01HL128914, K24HL105780, K23HL114724]
- American Heart Association [13EIA14220013]
- Fondation Leducq [14CVD01]
- Doris Duke Charitable Foundation [2014105]
Background Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. Methods and Results We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). FLNC encodes filamin Ca protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls. Conclusion We have identified a novel variant in FLNC as pathogenic variant for familial RCMa finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据