Molecular Epidemiology of Dilated Cardiomyopath

该建议通过确定疾病基因突变的频率、患者群体中的基因型/表型相关性及其临床相关性来解决扩张型心肌病的分子流行病学。特发性扩张型心肌病（DCM）是一种影响心肌的疾病，是导致心脏移植的心力衰竭的主要原因。DCM的病因主要是未知的，但这种疾病通常是遗传性的和遗传异质性的。连锁研究已经确定了17个FDC疾病位点，包括一个由pi绘制的位点我们在实验室对常染色体显性FDC大亲缘的第9号染色体进行了研究。到目前为止，已经确定了8种疾病基因：P.I.他的实验室发现了导致x连锁FDC的肌营养不良蛋白基因突变，最近在FDC和可变骨骼肌受累患者中发现了纤层蛋白A/C基因突变。其他研究者报道了导致FDC的心脏肌动蛋白、三角肌聚糖、desmin、他法嗪、-肌球蛋白重链和肌钙蛋白T的突变。然而，FDC和整个DCM人群中细胞骨架基因突变的患病率、类型和临床相关性尚不清楚。本申请提出一系列实验，旨在验证以下假设：1)基因突变是FDC的常见原因；2)不同的基因突变可能具有不同的频率、不同的预后价值和不同的临床相关性；3)几个FDC基因仍未被识别，它们可能编码细胞骨架蛋白。本研究的具体目的是：1)对FDC患者进行队列调查，并对其亲属进行评估，以确定遗传模式、表型、自然史，并招募分子遗传学研究人员；2)利用候选基因方法和定位候选克隆方法鉴定和表征导致FDC的新基因；3)通过研究FDC基因突变在具有或不具有家族性特征的大量患者群体中的流行率、类型和基因型/表型相关性，分析已知和新型疾病基因的分子流行病学。临床数据、DNA和FDC病例中的淋巴母细胞样细胞系已经从478名受试者中收集，我们预计每年将有20至30个新家庭入组。实验方法包括对已知和新的候选基因进行突变筛选，通过连锁和关联研究对9号染色体上的FDC基因进行定位克隆，使用为这些研究设计的大型数据库分析频率和基因型/表型相关性。识别导致DCM的基因和突变将极大地增加对这种疾病的分子基础的理解，并将允许开发新的基于分子的诊断和治疗策略。

This proposal addresses the molecular epidemiology of dilated cardiomyopathy by determining the frequency of disease gene mutations, and the genotype/phenotype correlations in the patient population, and their clinical relevance. Idiopathic dilated cardiomyopathy (DCM) is a disease affecting the cardiac muscle and is a primary cause of heart failure leading to heart transplant. The etiology of DCM is mainly unknown, but the disease is frequently inherited and genetically heterogeneous. Linkage studies have identified 17 FDC disease loci including a locus mapped by the P.I.'s laboratory on chromosome 9 in a large kindred with autosomal dominant FDC. Thus far, 8 disease genes have been identified: the P.I.'s laboratory has contributed to the discovery of mutations in dystrophin gene leading to X-linked FDC, and more recently, has discovered lamin A/C gene mutations in patients with FDC and variable skeletal muscle involvement. Other investigators have reported mutations in cardiac actin, delta-sarcoglycan, desmin, tafazzin, beta-myosin heavy chain and troponin T leading to FDC. However, the prevalence, type and clinical relevance of cytoskeletal gene mutations in FDC, and in the overall DCM population are unknown. This application proposes a series of experiments designed to test the following hypotheses: 1) gene mutations are a frequent cause of FDC, 2) different gene mutations may have different frequency, different prognostic value, and different clinical relevance, 3) several FDC genes are still unidentified, and they are likely to encode cytoskeletal proteins. The Specific Aims of this proposal are: 1) to investigate of a cohort of patients with FDC and to evaluate their relatives to determine the inheritance pattern, the phenotype, the natural history, and recruit for molecular genetics studies; 2) to identify and characterize novel genes causing FDC using a candidate gene approach and a positional candidate cloning approach; 3) to analyze the molecular epidemiology of known and novel disease genes by studying the prevalence, type, and genotype/phenotype correlation of the FDC gene mutations in a large patient population with or without a familial trait. Clinical data, DNA and, in the case of FDC, lymphoblastoid cell lines have already been collected from 478 subjects, and we anticipate the enrollment of 20 to 30 new families/year. The experimental methods include mutation screening of known and novel candidate genes, positional cloning of the FDC gene on chromosome 9 by linkage and association studies, analysis of the frequency and genotype/phenotype correlations using a large database designed for these studies. The identification of the genes and mutations responsible for DCM will greatly increase the understanding of the molecular basis of this disease and will allow for the development of new molecular- based diagnostic and therapeutic strategies.