The SCCOR will integrate genetic studies of valvular heart disease in human patients with mechanistic studies of valve development and maldevelopment in model systems. The proposal consists of 4 Projects and 2 Cores. Project 1: Genetic studies of valvular heart disease will use a multipoint variance-component linkage analysis to identify chromosomal regions linked to bicuspid aortic valve (BAV). Positional cloning of the gene causing canine tricuspid valve malformation (an analog of Ebstein anomaly) on canine chromosome 9 will lead directly to mutation analysis of the human homolog in probands with Ebstein anomaly. Project 2: The pathogenesis of PTPN11 mutations in human disease will expand the genotype-phenotype relations of PTPN11 mutations in cardiac patients with and without Noonan syndrome (NS). Additional human studies will be directed at identifying additional NS genes, and determining the effect of PTPN11 mutations on SHP-2 phosphatase activity in fibroblasts of NS patients. A knock-in of a PTPN11 mutant allele, Asn72Ser, will be performed in the mouse as a means to develop a model of NS. Project 3: Regulation of valvuloseptal development by DSCR1. The extent to which DSCR1 regulation by calcineurin/NFAT activation controls endocardial cushion remodeling and valvuloseptal development will be evaluated in mice trisomic for the DSCR1 locus and in cultured AV canal explants. These studies will provide genetic and molecular evidence for the role of DSCR1 in normal and abnormal valvuloseptal development. Project 4: Mechanisms of cardiac pathogenesis in Noonan syndrome will utilize mechanistic studies of SHP-2 mutations to define the pathogenic processes that underlie development of cardiovascular disease in humans with SHP-2 mutations. Comprehensive in vivo murine studies using inducible, cardiomyocyte- and endothelial-based expression of both normal and mutant SHP-2 will be utilized to achieve this goal. The Administrative Core (A) will serve as the organizational focus. The Phenotype - DNA Database Core (B) will develop and maintain an integrated central repository for information regarding probands with specific cardiac phenotypes that have been selected for their relationship to valvular heart disease. These reagents will facilitate hypothesis testing of novel candidate genes and genotype-phenotype correlations and thereby be a valuable resource for all Projects.
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