The complementary use of human genetics and model systems to understand disease-causing genes and the mechanisms that lead to disease holds great promise. A small number of genes causing congenital cardiovascular malformations (CCVMs) have been identified using genomewide linkage analysis in affected pedigrees, including the gene encoding a transcription factor, GATA4. In contrast to the limited number of genes identified through human studies, the recognition that key regulatory programs of cardiogenesis are conserved across species has led to the identification of over one hundred genes that, when mutated in model systems ranging from fruit flies to mice, cause defects in cardiac development. Approximately half are transcription factors. However, the contribution of genes encoding transcription factors to CCVMs and the precise mechanisms through which most of the essential genes function are largely unknown. In preliminary data, the PIs have undertaken a large-scale effort designed to translate the basic discoveries of the last decade into an understanding of the molecular basis of CCVMs. A screen of 60 patients with CCVM for sequence variations in 100 cardiac developmental genes resulted in identification of significant gene mutations in nearly half of all patients studied with at least one-third having demonstrable function-altering mutations. The PIs hypothesize that many of the human mutations in cardiac transcription factors significantly affect protein function and are likely to predispose to disease. In this project, they will test the hypothesis stated above for selected transcription factor mutations that are likely to be critical for human cardiogenesis. Specifically, they will build on the existing strengths of their lab and focus on the significance of human mutations in the hairy-related transcription factor, HRT2, GATA4 and the potent transcriptional activator, Myocardin (MYCD). By utilizing numerous available assays, the PIs will determine the mechanisms through which human mutations in these genes affect protein function in vitro and cardiogenesis in vivo, using both mouse and frog systems. Such studies will not only provide insight into the relevance of the human mutations, but will also reveal important structure-function aspects regarding the biology through which the cardiac regulatory proteins operate.
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