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.
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