IDENTIFICATION OF GENE DEFECTS THAT CAUSE FAMILIAL DILATED CARDIOMYOPATHIES

扩张型心肌病是一种主要的心肌疾病， 导致心脏增大，收缩功能受损， 经常会导致心力衰竭。最近的研究表明，大约 20%的扩张型心肌病是家族性的，是X连锁遗传的 或显性特征。而一些零星的扩张型心肌病病例 继发于毒素、感染或系统性疾病，在许多情况下 病原学不明。该项目建议使用分子 用遗传学方法鉴定编码基因的染色体(S) 可以突变以导致扩张型心肌病，这种病在 常染色体显性时尚(FDC)。使用位置克隆，我们将 找出导致这种情况的致病基因和突变。 我们还将评估FDC基因在导致非家族性心脏疾病中的作用 失败了。扩张型心肌病遗传病因的鉴定 将使有风险的家庭能够进行临床前诊断，并最终将 允许为这种情况开发可能会改善的动物模型 治疗方式。这个项目的目标是高度整合的 与此心力衰竭SCOR中其他项目的那些。身份识别 导致FDC的基因缺陷将使临床前识别 有心力衰竭风险的个体和促进这两项纵向研究 和预防性干预。此外，对遗传缺陷的识别 这导致FDC将促进基础研究，以阐明心肌细胞如何 结构和功能的改变是对突变的蛋白质和帮助 来定义补偿性反应。我们相信，理解 基因突变引发的复杂信号最终应该会提供 对收缩的分子机制的重要见解 导致心力衰竭的功能障碍。

Dilated cardiomyopathy is a primary disorder of the myocardium that produces cardiac enlargement with impaired systolic function that frequently causes heart failure. Recent studies suggest that approximately 20% of dilated cardiomyopathies are familial and inherited as an X-linked or dominant trait. While some sporadic cases of dilated cardiomyopathy occur secondary to toxins, infection, or systemic illness, in many instances the etiology is unknown. This project proposes to use molecular genetic approaches to identify the chromosome(s) that encode genes which can be mutated to cause dilated cardiomyopathies that are transmitted in an autosomal dominant fashion (FDC). Using positional cloning we will identify both the causal genes and mutations that produce this condition. We will also assess the role of the FDC genes in causing nonfamilial heart failure. Identification of the genetic cause of dilated cardiomyopathy will enable preclinical diagnosis in families at risk and will eventually permit development of animal models for this condition that may improve therapeutic modalities. The goals of this project are highly integrated with those of other projects in this Heart Failure SCOR. Identification of the gene defect responsible for FDC will enable preclinical recognition of individuals at risk for heart failure and foster both longitudinal studies and preventive interventions. Further, identification of a genetic defect that causes FDC will foster basic studies to elucidate how myocyte structure and function are altered in response to mutated proteins and help to define compensatory responses. We believe that understanding the complex signals triggered by gene mutation should ultimately provide important insights into the molecular mechanisms for contractile dysfunction that cause heart failure.