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Nature 424, 443-447 (24 July 2003) | doi:10.1038/nature01827; Received 25 March 2003; Accepted 18 June 2003; Published online 6 July 2003

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GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5

Vidu Garg1,2, Irfan S. Kathiriya1,2,3, Robert Barnes4, Marie K. Schluterman1, Isabelle N. King1, Cheryl A. Butler1, Caryn R. Rothrock1, Reenu S. Eapen1, Kayoko Hirayama-Yamada5, Kunitaka Joo6, Rumiko Matsuoka5,7, Jonathan C. Cohen4 & Deepak Srivastava1,3

  1. Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Rm. NA8.124, Dallas, Texas 75390-9148, USA
  2. Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA
  3. Department of Internal Medicine, and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, Texas 75390, USA
  4. The Heart Institute of Japan, Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan
  5. The Division of Genomic Medicine, Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan
  6. Department of Pediatrics, Kyusyu Kosei-Nenkin Hospital, Fukuoka 806-8501, Japan
  7. These authors contributed equally to this work

Correspondence to: Vidu Garg1,2Deepak Srivastava1,3 Correspondence and requests for materials should be addressed to V.G. (Email: Vidu.Garg@UTSouthwestern.edu) or D.S. (Email: Deepak.Srivastava@UTSouthwestern.edu).

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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.