Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns1. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs2,3. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation4,5,6,7, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects8,9. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.
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The authors thank both families for their participation; McDermott Center for Human Growth and Development for assistance with linkage analysis and sequencing; the Divisions of Pediatric Cardiology and Pediatric Cardiothoracic Surgery at Children's Medical Center of Dallas for assistance with clinical information and management; E. N. Olson and H. H. Hobbs for discussions and critical review of this manuscript; S. Johnson for graphic assistance; A. Garg for blood collection assistance; I. Komuro, R. J. Schwartz, S. R. Grant and E. N. Olson for plasmids; and S. Izumo for sharing unpublished data. This work was supported by a grant from NICHD/NIH to V.G.; grants from the NHLBI/NIH, March of Dimes Birth Defects Foundation, Smile Train Inc. and the Donald W. Reynolds Cardiovascular Clinical Research Center to D.S.; the NHLBI/NIH Programs for Genomic Applications to J.C.; and the Grant for the Promotion of the Advancement of Education and Research in Graduate Schools in Japan to R.M. I.N.K. is an NICHD/NIH fellow of the Pediatric Scientist Development Program. I.S.K. is a fellow of the NIH Medical Scientist Training Program.
The authors declare that they have no competing financial interests.
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Garg, V., Kathiriya, I., Barnes, R. et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424, 443–447 (2003). https://doi.org/10.1038/nature01827
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