Desmin mutation responsible for idiopathic dilated cardiomyopathy
Desmin mutation responsible for idiopathic dilated cardiomyopathy
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DOI：
10.1161/01.cir.100.5.461
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发表时间：
1999-08-03
期刊：
影响因子：
37.8
通讯作者：
Roberts, R
中科院分区：
文献类型：
--
作者：
Li, DX;Tapscoft, T;Roberts, R
背景-特发性扩张型心肌病是一种以心室扩张和收缩功能受损为特征的原发性心肌疾病，约20%的病例为家族性（FDCM）。它是心力衰竭和需要心脏移植的常见原因。虽然6个染色体位点负责常染色体显性遗传FDCM已被定位的连锁分析，这些基因还没有被确定。通过使用候选基因的方法，肌动蛋白最近被确定为负责扩张型心肌病。相当多的证据表明，结蛋白，肌肉特异性的中间丝，在心脏的生长和development.Methods和结果，以确定是否缺陷的结蛋白诱导扩张型心肌病，44先证者FDCM进行了临床评价和DNA分析中起着重要的作用。超声心动图检测的诊断标准包括心室直径大于或等于2.7 cm/m2，射血分数小于或等于50%，无其他潜在原因。通过聚合酶链反应扩增后，对结蛋白基因的外显子进行测序。错义结蛋白突变，Ile 451 Met，共分离与FDCM临床上没有明显的骨骼肌异常，被确定在一个4代家庭，但没有检测到在460无关的健康individuals.Conclusions-A新的错义结蛋白突变，Ile 451 Met，被确定为特发性扩张型心肌病的遗传原因。这一发现具有特别重要的意义，因为这是在结蛋白尾部结构域中检测到的第一个突变，并且结蛋白尾部的功能仍然未知。由于这种突变导致本报告中研究的家族中的限制性心脏表型，因此表明结蛋白的尾部在心脏组织中起着重要的功能作用。
Background-Idiopathic dilated cardiomyopathy, of which approximate to 20% of cases are familial (FDCM), is a primary myocardial disorder characterized by ventricular dilatation and impaired systolic function. it is a common cause of heart failure and the need for cardiac transplantation. Although 6 chromosomal loci responsible for autosomal dominant FDCM have been mapped by linkage analysis, none of these genes have been identified. By use of the candidate-gene approach, actin was identified recently as being responsible for dilated cardiomyopathy. Considerable evidence suggests desmin, a muscle-specific intermediate filament, plays a significant role in cardiac growth and development.Methods and Results-To determine whether a defect of desmin induces dilated cardiomyopathy, 44 probands with FDCM underwent clinical evaluation and DNA analysis. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of greater than or equal to 2.7 cm/m(2) with an ejection fraction less than or equal to 50% in the absence of other potential causes. After amplification by polymerase chain reaction, the exons of the desmin gene were sequenced. A missense desmin mutation, Ile451Met, which cosegregates with FDCM without clinically evident skeletal muscle abnormalities, was identified in a 4-generation family but was not detected in 460 unrelated healthy individuals.Conclusions-A novel missense mutation of desmin, Ile451Met, was identified as the genetic cause of idiopathic dilated cardiomyopathy. This finding is of particular significance because this is the first mutation detected in the desmin tail domain, and the function of the desmin tail remains unknown. Because this mutation leads to a restricted cardiac phenotype in the family studied in the present report, it suggests that the tail of desmin plays an important functional role in cardiac tissue.