Dilated cardiomyopathy (DCM) is a common disorder that causes heart failure and death. Hereditary factors contribute to the pathogenesis of DCM, and in some cases, DCM can be caused by the inheritance of a single gene. Recently, we demonstrated that DCM can result from mutations in the cardiac actin gene. This discovery suggests that defective force transmission in cardiac myocytes and episodic myocyte death can lead to heart failure. We have also discovered the chromosomal location of a second DCM locus, mapping this gene to the short arm of chromosome 3. The long-term goal of this work is to define novel genes responsible for DCM.
Specific Aims i nclude: 1. Ascertain and phenotypically characterize familial and sporadic cases of DCM.. Although we currently have sufficient patient material for initial linkage and mutational analyzes, continued ascertainment and clinical characterization will improve the likelihood of success during this project. 2. Chromosomal localization of novel DCM loci. Novel DCM loci will be identified using three strategies: a. cytogenetic analyses; b. genetic linkage analyses using DNA polymorphisms within candidate genes; c. genome-wide linkage analyses. 3. Identify novel DCM genes using three complementary approaches: a. the positional-candidate gene approach; b. the positional cloning approach; c. the candidate gene approach. Our first priority will be to identify the chromosome 3-linked DCM gene that we have identified using a positional-candidate gene approach or, if necessary, positional cloning. The second priority will be to define additional DCM genes using these three approaches. Based on the discovery that actin mutations use DCM, candidates include proteins important for force transmission within and between cardiac myocytes. These and other candidates will be tested using mutational analyses. 4. Define the genomic structure of novel DCM genes and complete mutational analyses in preparation for future genetic testing.
This aim will increase the feasibility of genetic testing. The work proposed here will facilitate prediction, prevention and treatment of DCM and may provide insight into the pathogenesis of common cardiomyopathies.
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