Congenital Heart Disease-Causing Gata4 Mutation Displays Functional Deficits In Vivo

Center for Cardiovascular and Pulmonary Research and the Heart Center, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, United States of America.
PLoS Genetics (Impact Factor: 7.53). 05/2012; 8(5):e1002690. DOI: 10.1371/journal.pgen.1002690
Source: PubMed


Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50% of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans.

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    • "This phenotype is distinct from the null GATA4 and myocardium-specific knockouts, but is similar to the FOG2 null phenotype (Tevosian et al., 2000), establishing a specific role for GATA4-FOG2 interaction in the development of coronary blood vessels. Another example of a physiologically important partnering of GATA4 was provided by the finding that the G296S mutation affects the interaction between GATA4 and Tbx5 and it leads to congenital heart disease in patients (Garg et al., 2003), while in homozygous mutant mice it causes mid-gestation lethality (Misra et al., 2012). "
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