Spectrum of heart disease associated with murine and human GATA4 mutation.
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.
Rajagopal
Satish K
SK
Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Ma
Qing
Q
Obler
Dita
D
Shen
Jie
J
Manichaikul
Ani
A
Tomita-Mitchell
Aoy
A
Boardman
Kari
K
Briggs
Christine
C
Garg
Vidu
V
Srivastava
Deepak
D
Goldmuntz
Elizabeth
E
Broman
Karl W
KW
Benson
D Woodrow
DW
Smoot
Leslie B
LB
Pu
William T
WT
D000818:Animals; D000831:Animals, Newborn; D018376:Cardiovascular Abnormalities / Q000235:genetics / Q000503:physiopathology; D004452:Echocardiography; D004622:Embryo, Mammalian / Q000002:abnormalities; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy
D050991:GATA4 Transcription Factor