X-linked dilated cardiomyopathy is a primary myocardial disease of unknown cause that has been reported by several investigators during the past decade and in retrospect, the likely cause of many previously described cases of """"""""idiopathic"""""""" cardiomyopathy. While no clinical or histopathological features of this disease differentiate it from other forms of dilated cardiomyopathy, the pattern of inheritance clearly differs from these other myocardial disorders in which autosomal dominant or autosomal recessive inheritance or nonfamilial sporadic causes has been shown. X-linked inheritance of this form of dilated cardiomyopathy is suggested by early-onset in males, late-onset in females, and no evidence of male-to-male transmission. The males demonstrate rapid progression to end-stage disease leading to death or cardiac transplantation. In this project, the gene causing X-linked dilated cardiomyopathy will be studied in a well-described pedigree in an attempt to locate and clone it. Blood has been obtained, DNA extracted with an automated DNA extractor, and lymphoblastoid cell line prepared for immortalization of the samples. Molecular genetic techniques, including Southern blotting, restriction fragment length polymorphism (RFLP) analysis, and linkage analysis will be initially employed to localize the gene locus on the X chromosome. At this time, 11 DNA probes exhibiting RFLPs have been utilized and linkage analysis initiated. Cloning of the gene will be attempted by genomic walking using flanking clones from either phage, cosmid, or YAC libraries after the gene locus is determined. The cloned gene will be sequenced and oligomers subsequently generated for use in the polymerase chain reaction (PCR). Successful mapping, cloning and sequencing the gene causing X- linked dilated cardiomyopathy would allow for improved premorbid and prenatal diagnosis using Southern analysis or PCR. In addition, the success of this project could provide improved understanding of the pathogenesis of this disorder and potentially provide insight into the mechanisms involved in other cardiomyopathies, including those associated with other X-linked diseases. A long term goal of this proposal is the discovery of the protein defect involved in this disorder, leading to development of medications specifically aimed at the cause of the disease and not merely its symptoms. This could eventually allow for therapeutic advances and improved longevity in these patients.
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