Left ventricular non-compaction (LVNC), a form of myocardium disease which presents in infancy as heart failure, is characterized as a hypertrophic and dilated left ventricle with systolic dysfunction, deep endomyocardial recesses and trabeculations, and in some patients, congenital heart disease (CHD). When CHD occurs, it most commonly includes atrial septal defect (ASD), ventricular septal defect (VSD), right heart obstruction, or hypoplastic left heart syndrome. This disorder may be inherited as an autosomal dominant or X-LINKED trait. In the X- linked form, the gene G4.5 which encodes the tafazzin protein, has been found to be mutated in some patients but the mechanism of disease has not been discovered. No gene(s) has been identified for the autosomal dominant form. In the subproject, families with LVNC will be recruited and the genes for the disease will be pursued using a primary candidate gene approach utilizing our """"""""final common pathway"""""""" hypothesis. In this hypothesis, we speculate that a central target protein is mutated directly or affected secondarily by an interacting cascade pathway, resulting in a specific phenotype. This hypothesis suggests that the final pathway or dilated cardiomyopathy is cytoskeletal/sarcolemmal abnormalities; hypertrophic cardiomyopathy is known to occur due to abnormalities of the sarcomere. Since these phenotypes are both involved in LVNC, genes encoding proteins involved in these pathways will be screened. In addition, this Program Project hypothesizes that transcription factors are disrupted in CHD, and therefore the interacting signaling cascade pathway(s) associated with the LVNC disease-causing gene will be identified. We have recently identified mutations in the alpha- dystrobrevin genes in patients with LVNC and this gene will be studied in a mutant mouse and the interacting proteins will be identified.
The specific aims of this subproject include: (1) Identification and recruitment of families with LVNC; (2) Identification and characterization of genes responsible of genes responsible for LVNC; (3) Development and characterization of mouse models of LVNC, including alpha- dystrobrevin; and (4) Identification of protein-protein interactions and characterization of the mechanisms and pathways leading to associated CHD. Appropriate transcription factors and signaling pathways, particularly those interacting with the TGF-beta pathway studied in the other subprojects. Completion of this subproject will improve our understanding of the """"""""final common pathways"""""""" involved in myocardial disease and CHD in children. In addition, successful completion of this subproject will clarify the role of signaling pathways in dilated and hypertrophic cardiomyopathy and lead to new paradigms in cardiac structure and function relationships.
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