Dilated cardiomyopathy (DCM) is a heterogeneous disorder that causes heart failure and death. In most cases it is likely that DCM is the result of acquired and inherited factor, but in some cases this disorder is clearly caused by the inheritance of a single gene. The long term goal of this project is to define the heritable causes of DCM by studying families with this disorder. Cases of familial and sporadic DCM will be identified, enrolled in the study, and phenotypically characterized. These new DCM families will be used with an established family to identify the chromosomal location of a DCM gene. Linkage analysis will be completed using polymorphic DNA markers that span the genome in a general search, but markers within or near candidate genes will also be pursued. Included in these analyses will be a new method, representational difference analysis, a technique which may dramatically affect both the speed and specificity of the linkage analysis. If complete linkage to a candidate gene is discovered, the candidacy of that gene will be tested using mutational analyses. Alternatively, if linkage to a DNA marker is defined with general linkage analysis, fine mapping of this chromosomal region will be completed. Once refined localization is established, previously cloned genes mapping to this region may become candidates for this region may become candidates for the disease gene. If necessary, cardiac cDNA libraries will be screened to identify additional candidate genes. Ultimately, the gene that causes DCM will be identified from genes mapping within the chromosomal region using mutational analysis. Chromosomal localization of a DCM gene will improve pre-symptomatic diagnosis of this disorder and is an essential first step toward identification of a disease gene. Identification of a DCM gene will help elucidate the mechanisms underlying this disorder and may lead to new strategies for prevention and treatment.
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