Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy.

Nathan R Tucker, Micheal A McLellan, Dongjian Hu, Jiangchuan Ye, Victoria A Parsons, Robert W Mills, Sebastian Clauss, Elena Dolmatova, Marisa A Shea, David J Milan, Nandita S Scott, Mark Lindsay, Steven A Lubitz, Ibrahim J Domian, James R Stone, Honghuang Lin, Patrick T Ellinor
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引用次数: 63

Abstract

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 C-a 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 RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.

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FLNC(丝蛋白C)新突变导致家族性限制性心肌病。
背景:限制性心肌病(RCM)是一种罕见的心肌病,其特征是舒张期心室功能受损,临床预后较差。很少有遗传形式的RCM被报道,并且在控制心肌细胞收缩功能的基因中发现了RCM的突变。方法:通过病史、体格检查、心电图和超声心动图对8个家族4代成员进行评估。受影响的个体表现为进行性RCM的多效综合征,房室间隔缺损和房颤的高患病率。5个受影响成员的外显子组测序在FLNC高度保守的残基中发现了一个新的错义变体(filamin C;p.V2297M)。FLNC编码丝蛋白c -一种蛋白质,它既是横纹肌中央收缩单元组装和组织的支架,也是细胞迁移和剪切应力过程中的机械敏感信号分子。对受影响家族成员心脏组织中FLNC定位的免疫组织化学分析显示,z盘定位减少,而插入盘的传统定位保留下来。干细胞衍生的心肌细胞突变携带效应等位基因,与对照相比收缩活性减弱。结论:我们已经确定了FLNC的一种新变异作为家族性rcm的致病变异,这一发现进一步扩展了这种罕见和病态心肌病的遗传基础。
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来源期刊
Circulation: Cardiovascular Genetics
Circulation: Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY
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审稿时长
6-12 weeks
期刊介绍: Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.
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