CLINICAL AND GENETIC DIVERSITY OF FAMILIAL DILATED CARDIOMYOPATHY

扩张型心肌病是一种原发性心肌疾病，可导致心脏增大并伴有收缩功能受损，并常导致心力衰竭。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，具有遗传病因。本项目将使用分子遗传学方法定义在染色体1、2和6上三个不同位点编码的家族性扩张型心肌病基因。定位克隆方法和候选分析将用于确定这些疾病位点上的突变基因。我们的方法将受益于与SCOR其他研究人员的密切互动，他们努力识别心力衰竭中受干扰的途径，这将为了解候选基因的性质提供重要线索。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。这些研究可能会导致更多疾病基因座的定义和其他疾病基因的鉴定。对遗传性心力衰竭及其相关表型的遗传病因的完整汇编对于发现这种知之甚少的综合征的新范式具有很大的潜力。识别疾病基因将改善对有患心力衰竭风险的个体的诊断，从而使纵向研究和预防干预成为可能。更广泛地说，在与dr。Michel, Neer， Ingwall和J. Seidman，发现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。了解由基因突变触发的复杂信号，最终将为了解由许多其他初始事件引发的心力衰竭的收缩功能障碍的分子机制提供重要的见解。

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.