Familial Dilated Cardiomyopathy: Detection/Gene Mapping

心力衰竭带来了相当大的发病率和死亡率，并消耗了大量的卫生保健资源，但心力衰竭的潜在分子机制仍不清楚。心力衰竭最常见的原因是扩张型心肌病，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%的家庭成员受到类似的影响。这种情况被称为家族性扩张型心肌病(FDC)，与遗传因素有关。事实上，对于常染色体显性遗传的FDC，已经涉及6个疾病基因(心脏肌动蛋白、结蛋白、层蛋白A/C、肌聚糖增量、β-肌球蛋白重链和心肌肌钙蛋白T)，并且遗传连锁已经确定了另外10个FDC基因座。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的分子机制还没有得到全面的了解。因此，鉴定更多与疾病相关的FDC基因势在必行。俄勒冈健康科学大学于1993年建立了FDC研究项目。我们前瞻性地确定了50个FDC家系，并对其临床特征进行了描述，其中5个是非裔美国人。在50人中，10人有6名或更多受影响的在世成员，40人有1-4名在世的受影响个人。已经选择了几个成人和儿童的大型家系进行基因定位。到目前为止，我们已经在两个FDC家族中发现了新的lamin A/C突变，在一个FDC家族中发现了心肌肌钙蛋白T的三个碱基对缺失。这次竞争性更新的具体目的是(1)进行临床筛查和对其他患有FDC的家系进行表征。识别大型FDC家族和获取成人和儿童临床心血管信息的所有临床程序，通常是通过我们小组进行的筛查活动，都已经到位，并经过了广泛的测试和优化。在临床筛查之后，受试者被归类为受影响、未受影响、未知或不确定。重点一直放在非裔美国人的FDC家系和基因座的鉴定和特征上，这是一个种族群体，尽管有严重的心脏病和更糟糕的预后，但进行的心肌病研究相对较少，而且没有报道有FDC的大家族。我们进一步建议(2)在几个FDC家系中定位与FDC有关的基因，其中的连锁和额外的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.