Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy.
Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy.
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DOI：
10.1161/circgenetics.117.001780
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Ellinor PT
中科院分区：
文献类型：
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作者：
Tucker NR;McLellan MA;Hu D;Ye J;Parsons VA;Mills RW;Clauss S;Dolmatova E;Shea MA;Milan DJ;Scott NS;Lindsay M;Lubitz SA;Domian IJ;Stone JR;Lin H;Ellinor PT
限制性心肌病（RCM）是一种罕见的心肌病，其特征是舒张功能受损，导致临床预后不良。罕见的是，遗传形式的RCM已被报道和突变的RCM已被确定的基因，管理心肌细胞的收缩功能。我们评估了8个家庭成员跨越四代的历史，体格检查，心电图和超声心动图。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的高度保守残基（p.V2297M）中鉴定出单个新的错义变体。FLNC编码细丝蛋白C，细丝蛋白C是一种既作为横纹肌中央收缩单位组装和组织的支架，又作为细胞迁移和剪切应力期间的机械敏感性信号分子的蛋白质。免疫组化分析细丝蛋白C定位在心脏组织中的受影响的家庭成员揭示了减少本地化的z盘，而传统的本地化在闰盘被保存。与对照组相比，突变携带效应等位基因的干细胞衍生的心肌细胞收缩活性降低。我们已经确定了FLNC中的一种新变体作为家族性RCM的致病性变体，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。
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. We evaluated 8 family members across four 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 (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 Filamin C 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 to controls. We have identified a novel variant in FLNC as pathogenic variant for familial RCM, a finding that further expands upon the genetic basis of this rare and morbid cardiomyopathy.