Hypertrophic cardiomyopathy (HCM) is an autosomal dominant primary muscle disease characterized by cellular and myofibrillar disarray and increased muscle mass, predominantly of the cardiac septum. In the young, HCM is the most common cause of sudden death and in older affected individuals a common cause of cardiac failure. The overall objective of this project is to localize, identify, an clone the gene causing HCM and to characterize the pathophysiology of this disease. Individuals in families with HCM subsequent to being identified will undergo clinical and echocardiographic examination, as well as provide the necessary blood specimens to establish transformed lymphoblastoid lines as a renewable source of DNA. Linkage analysis with classical markers and restriction fragment length polymorphisms (RFLPs) will be used to localize the HCM gene to a specific chromosomal region. A detailed linkage map on each side of the HCM locus will be established and flanking DNA clones within 1 cM of the locus will be identified. If necessary, new probes will be cloned from chromosome specific libraries, RFLPs identified, and linkage to HCM determined in order to develop the closely flanking markers. A series of overlapping DNA clones from the region determined by the two most closely flanking probes will be established using phage, cosmid, or yeast artificial chromosome (YAC) vectors. The HCM gene will be identified by screening the overlapping clones for sequences which are conserved across species, expressed in cardiac muscle, contain open reading frames, and are altered in individuals with HCM. The HCM gene will be used to isolate the corresponding cDNA from a cardiac muscle library and to determine the pathophysiology of HCM. Isolation of markers closely linked to the HCM gene will provide the necessary first step in developing an accurate presymptomatic and prenatal diagnosis of HCM and a method to determine the penetrance and delineate any genetic heterogeneity. Cloning the gene for HCM and elucidation of its pathophysiology will allow the design of rational therapy for this disease. Understanding the etiology and pathogenesis of HCM will provide a key to understanding cardiac hypertrophy and failure resulting from a wide variety of different primary diseases.
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