Abstract 3404: Loss of Gata-5 in Mice Leads to Congenital Heart Disease and Reveals Genetic Epistasis with Gata-4 and Gata-6
Congenital heart defects in humans occur in 1% of live birth. The majority involve the valves and septa, which originate from endocardial cells. Three members of the GATA family of transcription factors, GATA-4, 5 and 6 are expressed in the heart. The essential roles of GATA-4 and -6 in the mammalian heart are well established but the exact function of GATA-5, which is present mainly in endocardial cells, remains undefined. The objective of this study is to analyze the consequence of inactivation of GATA-5 on heart development and elucidate the molecular basis of GATA-5 function in the endocardium. To inactivate the mouse GATA-5 gene, a targeting construct that deletes the second zing finger, which is essential for DNA binding and transcriptional activity, has been generated. GATA-5 null mice were viable and obtained at the expected Mendelian ratios. Functional and biochemical cardiac parameters were assessed using echocardiography, electrocardiogram and RNA analysis at baseline level. Electrophysiology results indicate that GATA-5 null mice have an elevated QTc interval, suggesting that the duration of activation and recovery of the ventricular muscle is affected. Echocardiographic analysis revealed congenital malformation of the heart valves, which were associated with left ventricular hypertrophy. Histological examination and biochemical analysis of hypertrophy markers confirmed these results. Moreover, while mice lacking one GATA-5 allele show limited cardiac abnormalities, compound deletion of one GATA-5 allele and one GATA-4 or one GATA-6 allele appear to be incompatible with embryonic development. The presentation will address the likely mechanisms that are disrupted in endocardial cells and that can account for the observed phenotypes. These studies indicate that GATA-5 is essential for proper heart formation and reveal that compound alteration of any two cardiac GATA factors is incompatible with embryonic development. The data also identify GATA-5 as a potential congenital heart disease causing gene in human.