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. 2007 Dec;43(6):677-85.
doi: 10.1016/j.yjmcc.2007.06.004. Epub 2007 Jun 21.

Spectrum of Heart Disease Associated With Murine and Human GATA4 Mutation

Free PMC article

Spectrum of Heart Disease Associated With Murine and Human GATA4 Mutation

Satish K Rajagopal et al. J Mol Cell Cardiol. .
Free PMC article


The transcription factor GATA4 is essential for heart morphogenesis. Heterozygous mutation of GATA4 causes familial septal defects. However, the phenotypic spectrum of heterozygous GATA4 mutation is not known. In this study, we defined the cardiac phenotypes that result from heterozygous mutation of murine Gata4. We then asked if GATA4 mutation occurs in humans with these forms of congenital heart disease (CHD). In mice, heterozygous Gata4 mutation was associated with atrial and ventricular septal defect (ASD, VSD), endocardial cushion defect (ECD), RV hypoplasia, and cardiomyopathy. Genetic background strongly influenced the expression of ECD and cardiomyopathy, indicating the presence of important genetic modifiers. In humans, non-synonymous GATA4 sequence variants were associated with ECD (2/43), ASD (1/8), and RV hypoplasia in the context of double inlet left ventricle (1/9), forms of CHD that overlapped with abnormalities seen in the mouse model. These variants were not found in at least 500 control chromosomes, and encode proteins with non-conservative amino acid substitutions at phylogenetically conserved positions, suggesting that they are disease-causing mutations. Cardiomyopathy was not associated with GATA4 mutation in humans. These data establish the phenotypic spectrum of heterozygous Gata4 mutation in mice, and suggest that heterozygous GATA4 mutation leads to partially overlapping phenotypes in humans. Additional studies will be required to determine the degree to which GATA4 mutation contributes to human CHD characterized by ECD or RV hypoplasia.

Conflict of interest statement

Conflicts of Interest: none.


Figure 1
Figure 1. Gata4 protein expression in WT and G4D fetal hearts
Gata4 protein in E14.5 WT and G4D hearts was measured by Western blotting. In G4D hearts, expression of full length Gata4 protein (arrow) was reduced. A truncated protein lacking the N-terminal activation domain was expressed in G4D fetal hearts (arrowhead). Expression was not different in C57 and FVB strain backgrounds.
Figure 2
Figure 2. Perinatal death of Gata4 mutant mice
a. Frequency of G4D or WT genotypes at weaning in the C57 strain background. The expected Mendelian frequency was 50% (dashed line). b. Perinatal attrition of G4D mice in the C57 background. 141 births produced 56 G4D mice, of which 52% died, and 63 WT, of which 18% died. 22 pups were cannabilized as neonates and could not be genotyped. c. Hearts from deceased WT and G4D-C57 neonates. The middle panel shows an ASD primum defect (arrow). The right panel shows a markedly hypoplastic RV. The RV apex (arrow) is distinct from the LV apex. There is also a CAVC defect (asterisk) that is malaligned so that it opens mostly into the LV.
Figure 3
Figure 3. ECDs in G4D-C57 late gestation embryos
a–e. Hematoxylin and eosin stained sections demonstrating a spectrum of ECDs. a. WT control. b. Well-balanced CAVC canal defect. c. CAVC defect opening mainly into the left ventricle. The RV is moderately hypoplastic. d. Inlet VSD. The atrial septum is intact, and there are two AV valves, albeit with highly primitive leaflets (arrowhead). The ventricular portion of the AV canal is not septated, resulting in an inlet VSD (arrow). e. ASD primum (arrow) and ASD secundum (arrowhead). The ventricular portion of the AV canal is septated.
Figure 4
Figure 4. RV hypoplasia in G4D-C57 late gestation embryo
Adjacent sections from an E18.5 WT-C57 (left box of six images) or G4D-C57 littermate (right box of six images). Myocardium was visualized by desmin immunostaining, and counterstained with hematoxylin. Numbers indicate order of sections. The hypoplastic inflow portion of the RV is shown in sections 1 and 2. The outflow portion of the RV was normal in size (sections 5 and 6). In this heart, RV hypoplasia occurred in association with CAVC (section 3).

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