MOLECULAR MECHANISMS OF VALVE DEVELOPMENT AND DISEASE

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This is a clinical project that will study valvular heart disease, a common clinical problem carrying substantial morbidity and mortality. Valve malformations are frequently recognized as birth defects, and a growing body of evidence suggests that valve disease discovered later in life may also have origins during valvulogenesis. The objective of this project is to use a genetic linkage-positional cloning approach to identify genetic loci and ultimately ascertain the identity of gene mutations in humans. The emphasis is on two types of valvular heart disease: bicuspid aortic valve (BAV) and Ebstein anomaly. The commonality of genes and signal pathways in valve development of both the outflow tract and the AV canal provides a rationale for the study of both the semilunar and AV valves. Several observations suggest that both BAV and Ebstein anomaly have a genetic cause, but little progress has been made toward identifying susceptibility loci. In AIM 1 and AIM 2 variance component linkage analysis and positional cloning studies will be performed on 170 kindreds with BAV, participants will undergo complete clinical evaluation including echocardiography. In preliminary studies, 50 kindreds have already been identified. AIM 3 is a linkage-positional cloning study of Ebstein anomaly. Since human kindreds suitable for mapping have not been identified, we studied a dog kindred with tricuspid valve malformation (CTVM, the dog analog of Ebstein anomaly) and identified a susceptibility locus on dog chromosome 9 (CFA9) in a region homologous to human chromosome 17q11-23. Mutation analysis of the human homolog of the CTVM gene will be carried out in 50 probands with Ebstein anomaly. Mechanistic studies of known disease candidate genes will be performed in AIM 4 using an endocardial cushion maturation and remodeling assay. Such studies are an essential component of translational research as they provide a link to developmental mechanisms that are essential for defining pathogenesis. Ultimately the taxonomy of valve disease may relate more to genetic cause and pathogenetic mechanism than to clinical phenotype at the time of diagnosis. A revised valve disease taxonomy based on pathogenesis may provide opportunities to develop therapeutic strategies founded on molecular mechanisms rather than end-stage clinical phenotype.