Abstract 3409: The Human GATA4 G296S Mutation Disrupts Mouse Cardiac Morphogenesis
Cardiac septal defects (CSD) are the most frequent form of congenital heart disease in children, accounting for almost 50% of all cases. We previously reported a heterozygous G296S missense mutation of the transcription factor, GATA4, in a large family with CSD (Garg et al., 2003). In vitro studies demonstrated the mutant GATA4 protein has reduced DNA binding activity and does not interact with the cardiac transcription factor, TBX5. To investigate the molecular and in vivo deficits of this point mutation, we generated a mouse harboring the same mutation, Gata4 G295S. Homozygous Gata4-null mice have previously been reported to have cardiac bifida and exhibit defects in ventral morphogenesis. These defects are proposed to be due to abnormal Gata4 function in the endoderm. However, mice homozygous for Gata4 G295S have normal ventral body patterning and develop until approximately embryonic day 9.5, after which normal Mendelian ratios are not observed. Homozygous Gata4 G295S embryos display a looped heart tube, but have thin ventricular myocardium and a single ventricular chamber. GATA4 protein levels are unchanged in the homozygous Gata4 G295S mutant embryos when compared to wildtype littermates. The cardiac abnormalities and the absence of ventral body patterning defects suggest the Gata4 G295S mutant protein can sufficiently activate downstream targets of Gata4 in the endoderm but not mesoderm. To investigate the functional role of the Gata4 G295S mutation in different cell lineages we generated mice heterozygous for Gata4 G295S and Gata4 deletion in early embryonic myocardium, late embryonic myocardium and endocardium using Nkx2.5-Cre, MHC-Cre or Tie2-Cre respectively. Phenotypic characterization of these mice will be performed. In summary, the Gata4 G295S allele functions as a hypomorph in the mesoderm, and disrupts proper cardiac morphogenesis. This phenotype may be due to the inability of the Gata4 G295S protein to interact with Tbx5 in the early myocardium, suggesting that the interaction between Gata4 and Tbx5 in the mesoderm plays an important role in early cardiac formation.
This research has received full or partial funding support from the American Heart Association, AHA National Center.