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Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect

机译:限制性心肌病是由新型纯合的脱霉素(DES)突变P.Y122H引起严重的长丝组装缺陷引起的

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摘要

Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.
机译:在这里,我们展示了一个小伊朗家族,指数患者与房室(AV)块组合接受限制性心肌病(RCM)的诊断。遗传分析揭示了DES基因(C.364T> C; P.Y122H)中的新型纯合物畸变突变,其在人口数据库中不存在。突变是在高度保守的线圈1脱霉亚域中定位的。在硅中,预测工具表明Desmin(DES)突变P.y122h的有害效果。因此,我们产生编码形成的突变体和野生型Desmin的表达质粒,并分析衍生自诱导多能干细胞和HT-1080细胞的心肌细胞体外的长丝形成。共聚焦显微镜揭示了突变体Desmin的严重长丝组装缺陷,其支持DES突变,P.Y122H的致病性,而野生型Desmin形成规则的中间细丝。根据美国医学遗传学和基因组学学院的指导方针,我们将这种突变分类为一种新的致病性突变。我们的报告可以指出DES突变的隐性遗传,P.Y122H,这对于由于DES突变引起的具有限制性心肌病的类似家庭的遗传咨询很重要。

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