Familial Dilated Cardiomyopathy: Detection/Gene Mapping

心衰的发病率和死亡率很高，并消耗大量的医疗资源，但心衰的潜在分子机制仍不清楚。心衰最常见的结果是扩张型心肌病，一种常见的形式是特发性扩张型心肌病（IDC）。在IDC患者中，20- 50%的患者有类似的家庭成员。这种情况，被称为家族性扩张型心肌病（FDC），涉及遗传原因。事实上，对于常染色体显性遗传的FDC，涉及6个疾病基因（心脏肌动蛋白、desmin、层粘连蛋白A/C、-肌聚糖、-肌球蛋白重链和心脏肌钙蛋白T），并且遗传关联已确定了10个额外的FDC位点。尽管取得了这些进展，但这些疾病基因很可能只代表了FDC病例的一小部分，而且对FDC的分子机制还没有全面的了解。因此，鉴定其他疾病相关的FDC基因是必要的。1993年在俄勒冈健康科学大学建立了一个FDC研究项目。我们对50个FDC家族进行了前瞻性鉴定和临床特征分析，其中5个是非裔美国人。在这50个组织中，10个组织有6个或更多在世的受影响成员，40个组织有1-4个在世的受影响个体。已经选择了几个大的成人和儿童谱系进行基因定位。到目前为止，我们已经在两个FDC家族中发现了新的纤层蛋白A/C突变，在一个FDC家族中发现了心脏肌钙蛋白T的三个碱基对缺失。这项竞争性更新的具体目标是：(1)对FDC的其他谱系进行临床筛查和表征。通常通过我们小组开展的筛查活动，确定FDC大家族并获得成人和儿童临床心血管信息的所有临床流程都已到位，并已进行了广泛的测试和优化。临床筛选后，受试者分为受影响、未受影响、未知或不确定。重点放在非裔美国人FDC谱系和基因座的鉴定和表征上，该种族的心肌病研究相对较少，尽管有大量心脏疾病的预后较差，而且没有FDC的大家庭报告。我们进一步建议(2)在几个FDC家系中定位FDC的基因，其中的连锁和其他基因定位研究正在进行中。

Heart failure brings considerable morbidity and mortality and consumes a large quantity of health care resources, yet the underlying molecular mechanisms of heart failure remain poorly defined. Heart failure results most commonly from dilated cardiomyopathy, and one common form is idiopathic dilated cardiomyopathy (IDC). Of patients with IDC, 20-50 percent have family members similarly affected. This condition, termed familial dilated cardiomyopathy (FDC), implicates a genetic cause. Indeed, for FDC with autosomal dominant inheritance, six disease genes (cardiac actin, desmin, lamin A/C, delta- sarcoglycan, beta-myosin heavy chain, and cardiac troponin T) have been implicated, and genetic linkage has identified 10 additional FDC loci. Despite this progress, it is likely that the these disease genes represent a only fraction of FDC cases, and a comprehensive understanding of the molecular mechanisms for FDC has not yet been achieved. Thus, identification of additional disease-associated FDC genes is imperative. An FDC research program was established in 1993 at Oregon Health Sciences University. We have prospectively identified and clinically characterized 50 FDC families of which five are African-American. Of the 50, 10 have 6 or more living affected members and 40 have 1-4 living, affected individuals. Several large pedigrees of adults and children have been selected for gene mapping. To date we have identified novel lamin A/C mutations in two FDC families, and a three base pair deletion in cardiac troponin T in one FDC family. The specific aims of this competitive renewal are to (1) perform clinical screening and characterization of additional pedigrees with FDC. All clinical processes to identify large FDC families and to obtain clinical cardiovascular information of both adults and children, usually through screening activities conducted by our group, are in place and have been extensively tested and optimized. Following clinical screening, subjects are categorized as affected, unaffected, unknown or indeterminate. Emphasis has been placed on the identification and characterization of FDC pedigrees and loci in African-Americans, a racial group where relatively little cardiomyopathy research has been performed despite substantial cardiac disease with worse outcomes, and no large families have been reported with FDC. We further propose to (2) map the genes responsible for FDC in several FDC pedigrees, of which linkage and additional gene mapping studies are in progress.