GATA6 Regulates Aortic Valve Remodeling and its Haploinsufficiency Leads to RL-Type Bicuspid Aortic Valve

Background -Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1-2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and the mechanisms of BAV etiology and pathogenesis remain largely undefined. Methods -Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS study. GATA6 expression was determined in mice and human tissues using qRT-PCR and immunohistochemistry. Mechanistic studies were carried out in cultured cells. Results -Gata6 heterozygous mice have highly penetrant RL type BAV, the most frequent type in human. GATA6 transcript levels are lower in human BAV as compared to normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes as loss of one Gata6 allele from Isl-1 positive cells- but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice. Conclusions -The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.