Original articleSpectrum of heart disease associated with murine and human GATA4 mutation
Introduction
The morphogenetic complexity of fashioning a four-chambered heart from a straight tube mandates a precisely orchestrated interplay of multiple transcription factors, adhesion molecules, ion channels, signaling molecules and structural proteins [1]. Errors in this process result in congenital heart disease (CHD), the most common form of birth defect. Mutation of a small but growing number of genes has been shown to cause CHD [2]. Recently, mutation of the zinc finger transcription factor GATA4 was shown to cause atrial and ventricular septal defects in several unrelated extended pedigrees (Table 1) [3], [4], [5], [6]. Among CHD patients without a family history (“sporadic” CHD), GATA4 mutations appear to be infrequent. In published studies of sporadic CHD, GATA4 mutations were found in only 2 out of 376 probands examined (Table 1) [7], [8], [9], [10]. However, without prior knowledge of the phenotypic spectrum of GATA4 mutation, it was not possible to target these studies to forms of CHD most likely to be caused by GATA4 mutation. Therefore GATA4 mutation may be more frequently associated with specific forms of CHD that are not well represented in current literature.
We studied the spectrum of cardiac abnormalities found in mice with mutation of one copy of GATA4. We found that heterozygous GATA4 mutation in mice caused endocardial cushion defect (ECD), atrial or ventricular septal defect (ASD or VSD), hypoplastic right ventricle, and cardiomyopathy. Reasoning that this might give insight into the types of heart defects that might be caused by GATA4 mutation in humans, we then looked for GATA4 mutations in patients with similar forms of CHD. We found non-synonymous GATA4 sequence variants in association with ECD, hypoplastic RV in the context of double inlet left ventricle (DILV), and ASD. These results refine our understanding of the phenotypic spectrum of GATA4 mutation.
Section snippets
Mice
The Gata4Δex2 allele has been described [11]. Mice were backcrossed for more than 7 generations into either the C57BL6/J (abbreviated C57; Jackson Labs) or the FVB/NCrl (FVB; Charles River Labs) genetic backgrounds. Structural abnormalities were diagnosed on H&E-stained serial paraffin sections. Echocardiography was performed on unsedated 8-week-old mice. Mice were held in a supine position and imaged with a 15-MHz probe. All analyses were performed blinded to genotype. Animal use was according
Murine model of Gata4 mutation
The mutant Gata4 allele used in this study, Gata4Δex2, contains a deletion of the start codon and 46% of the coding region [11], [15]. This allele does not express full-length protein. In fetal heart, but not in adult heart, the allele does express a truncated protein lacking the essential N-terminal transcriptional activation domain (Fig. 1) [15]. In vitro reporter assays showed loss of transcriptional activity and did not suggest dominant negative activity [15]. Prior in vivo characterization
Spectrum of phenotypes associated with murine Gata4 mutation
Using tissue-restricted gene inactivation approaches, we previously showed that Gata4 is required in the myocardial compartment for normal myocardial growth and RV morphogenesis [24], and in endocardially derived structures for normal atrioventricular valve development [15]. These processes were also disrupted by a hypomorphic mutation of Gata4, which reduced Gata4 protein by 70% and resulted in embryonic lethality due to defects in myocardial growth, endocardial cushion development, and
Acknowledgments
This work was supported by grants from the NIH (SKR, NIH training grant T32HLO07572; WTP, SCCOR P50HLO74734; DWB SCCOR P50HL74728 and HL69712; and EG SCCOR P50HL74731). WTP was also supported by charitable donations from Edward Marran and Karen Carpenter. Jie Shen was supported as a Bang Bao Research Scholar by a grant from Proctor and Gamble. We thank M. Sarkar, C. Seidman, and J. Seidman for unpublished data.
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- 1
Current address: Cardiology Department, Shanghai Children’s Hospital, Shanghai Jiaotong University, 24 Lane 1400 Western Beijing Road, Shanghai 200040, China.
- 2
Current address: Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
- 3
Current address: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.