Abstract 2168: Identification of Mutations in GATA6 as a Novel Genetic Cause of Congenital Cardiac Outflow Tract Defects
Congenital heart diseases (CHD) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. Although improved understanding of genetic causes would provide insight into the pathobiological basis of CHD, the underlying genetic etiology of most CHD are still unknown. Here we show that mutations in the gene encoding the transcription factor GATA6 cause CHD. We screened GATA6 mutation in 102 patients with CHD involving typical cardiac outflow tract (OFT) development, PTA or PAVSD, and identified three novel GATA6 mutations, E142K, N466H and E486del, in three independent probands. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) were shown to be regulated directly by GATA6, and all of GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis suggests that, in the developing heart, the expression of SEMA3C in the OFT/subpulmonary myocardium and PLXNA2 in the cardiac neural crest contributing to the OFT is dependent on GATA transcription factors. Together, our data implicate mutations in GATA6 as a novel genetic cause of CHD and as a direct regulator of the neurovascular signaling essential for cardiogenesis. We believe that the inactivation of GATA6-dependent semaphorin-plexin signaling may affect the cardiac neural crest development, especially in the region of OFT. The GATA6-centered regulatory mechanism during cardiogenesis provides a novel insight on the pathogenesis of CHD that eventually leads to preventive and regenerative interventions for these common birth defects.