CLINICAL AND GENETIC DIVERSITY OF FAMILIAL DILATED CARDIOMYOPATHY

扩张型心肌病是一种主要的心肌疾病，会导致心脏增大，收缩功能受损，并经常发生心力衰竭。在这种病理的多种原因中，越来越多的证据表明，20-35%的扩张型心肌病是家族性的，并有遗传病因。本项目将使用分子遗传学方法确定在1、2和6号染色体上的三个不同位点编码的家族性扩张型心肌病基因。将采用位置克隆方法和候选分析来确定这些疾病基因座上的突变基因。我们的方法将受益于与SCOR中其他研究人员的密切互动，他们识别心力衰竭干扰途径的努力应该会提供关于候选基因性质的重要线索。项目1还将广泛利用核心B和C提供的专业知识和技术，以充分阐明人类这种病理的临床谱系。这些研究可能会导致对其他疾病基因的定义和其他疾病基因的识别。汇编遗传性心力衰竭及其相关表型的完整遗传病因谱，对于发现关于这种鲜为人知的综合征的新范式具有巨大的潜力。疾病基因的识别将改善对有发生心力衰竭风险的个人的诊断，这将使纵向研究和预防性干预成为可能。更广泛地说，与Michel、Neer、Ingwall和J.Seidman博士合作，识别导致人类心力衰竭的基因缺陷将有助于阐明心肌细胞对突变蛋白的细胞和分子反应。了解基因突变触发的复杂信号最终将为了解收缩功能障碍的分子机制提供重要的见解，收缩功能障碍是由许多其他启动事件引发的心力衰竭。

Dilated cardiomyopathy is a primary disorder of the myocardium that produces cardiac enlargement with impaired systolic function, and frequently heart failure. Of the multiple causes for this pathology, increasing evidence indicates 20-35% of dilated cardiomyopathies are familial and have a genetic etiology. This project will use molecular genetic approaches to define familial dilated cardiomyopathy genes encoded at three distinct loci on chromosomes 1, 2, and 6. Positional cloning approaches and candidate analysis will be employed to define mutated genes at these disease loci. Our approaches will benefit from the close interactions with other investigators in the SCOR, whose efforts to identify pathways perturbed in heart failure should provide important clues regarding the nature of candidate genes. Project 1 will also make extensive use of the expertise and technologies provide in Cores B and C to fully elucidate the clinical spectrum of this pathology in humans. These studies will likely result in the definition of additional disease loci and the identification of other disease genes. Compilation of a full repertoire of genetic etiologies for inherited forms of heart failure and their associated phenotypes has great potential for discovering new paradigms about this poorly understood syndrome. Identification of disease genes will improve diagnosis of individuals at risk for developing heart failure which will enable longitudinal study and enable preventive interventions. More broadly, and in collaboration with Drs. Michel, Neer, Ingwall and J. Seidman, identification of gene defects that cause human heart failure will help to elucidate the cell and molecular responses of the myocyte to mutated proteins. Understanding the complex signals triggered by gene mutations should ultimately provide important insight into the molecular mechanisms for contractile dysfunction that cause heart failure incited by many other initiating events.