Familial Dilated Cardiomyopathy: Detection/Gene Mapping

心力衰竭的发病率和死亡率相当高，消耗了大量的医疗资源，但心力衰竭的分子机制仍不清楚。 心力衰竭最常见于扩张型心肌病，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影响。 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、结蛋白、核纤层蛋白A/C、δ-肌聚糖、β-肌球蛋白重链和心肌肌钙蛋白T），遗传连锁已确定了10个额外的FDC基因座。 尽管取得了这一进展，但这些疾病基因可能仅代表FDC病例的一小部分，并且尚未实现对FDC分子机制的全面理解。 因此，鉴定其他疾病相关FDC基因势在必行。 1993年，俄勒冈州健康科学大学建立了FDC研究项目。 我们已经前瞻性地确定和临床特征的50个FDC家庭，其中五个是非洲裔美国人。 在这50人中，10人有6名或6名以上受影响的成员，40人有1-4名受影响的成员。 已经选择了几个成人和儿童的大谱系进行基因作图。 到目前为止，我们已经确定了新的核纤层蛋白A/C突变在两个FDC家庭，和一个三个碱基对缺失的心脏肌钙蛋白T在一个FDC家庭。 本次竞争性更新的具体目的是（1）对其他FDC家系进行临床筛选和表征。 通常通过我们小组进行的筛查活动，识别大FDC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，受试者被分类为受累、未受累、未知或不确定。 重点放在非裔美国人FDC家系和基因座的鉴定和表征上，尽管存在大量心脏病，结局更差，但对非裔美国人进行的心肌病研究相对较少，并且没有FDC大家族的报告。 我们进一步建议（2）在几个FDC家系中定位负责FDC的基因，其中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.