title: Spectrum of heart disease associated with murine and human GATA4 mutation.
abstract: 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.
authors.affiliation: Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Rajagopal
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Dita
authors.initials: D
authors.lastname: Obler
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.forename: Aoy
authors.initials: A
authors.lastname: Tomita-Mitchell
authors.forename: Kari
authors.initials: K
authors.lastname: Boardman
authors.forename: Christine
authors.initials: C
authors.lastname: Briggs
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.forename: Karl W
authors.initials: KW
authors.lastname: Broman
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Smoot
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
mesh_terms: 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
chemical_list: D050991:GATA4 Transcription Factor