Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 43, Issue 6, Pages 677-685Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2007.06.004
Keywords
animal models; congenital heart defects; cardiac development; genetics of congenital heart disease
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Funding
- NHLBI NIH HHS [P50 HL074731, P50 HL 074734, T32 HL 007572, HL 69712, P50 HL 74728, P50 HL074734-05, T32 HL007572, P50 HL 74731, P50 HL074734, K24 HL069712, P50 HL074728] Funding Source: Medline
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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. (c) 2007 Elsevier Inc. All rights reserved.
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