@article{6a92ab981e4a45b79f8e2b92b692c947,
title = "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5",
abstract = "Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. 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 formation, 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 defects. 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.",
author = "Vidu Garg and Kathiriya, {Irfan S.} and Robert Barnes and Schluterman, {Marie K.} and King, {Isabelle N.} and Butler, {Cheryl A.} and Rothrock, {Caryn R.} and Eapen, {Reenu S.} and Kayoko Hirayama-Yamada and Kunitaka Joo and Rumiko Matsuoka and Cohen, {Jonathan C.} and Deepak Srivastava",
note = "Funding Information: Acknowledgements We thank J. Harada, T. Kellogg, B. Reinhart and members of the Sinha lab for comments on the manuscript; T. Metcalf and E. Sandoval for plant materials; and E. Dean and the UC Davis John Tucker herbarium. This work was supported by Jastro Shields and Elsie Stocking fellowships to M.K., and by awards from the NSF to N.R.S. Funding Information: Acknowledgements 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{\textquoteright}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. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.",
year = "2003",
month = jul,
day = "24",
doi = "10.1038/nature01827",
language = "English (US)",
volume = "424",
pages = "443--447",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6947",
}