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

Vidu Garg (), Irfan S. Kathiriya, Robert Barnes, Marie K. Schluterman, Isabelle N. King, Cheryl A. Butler, Caryn R. Rothrock, Reenu S. Eapen, Kayoko Hirayama-Yamada, Kunitaka Joo, Rumiko Matsuoka, Jonathan C. Cohen and Deepak Srivastava ()
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Vidu Garg: University of Texas Southwestern Medical Center at Dallas
Irfan S. Kathiriya: University of Texas Southwestern Medical Center at Dallas
Robert Barnes: University of Texas Southwestern Medical Center at Dallas
Marie K. Schluterman: University of Texas Southwestern Medical Center at Dallas
Isabelle N. King: University of Texas Southwestern Medical Center at Dallas
Cheryl A. Butler: University of Texas Southwestern Medical Center at Dallas
Caryn R. Rothrock: University of Texas Southwestern Medical Center at Dallas
Reenu S. Eapen: University of Texas Southwestern Medical Center at Dallas
Kayoko Hirayama-Yamada: Tokyo Women's Medical University
Kunitaka Joo: Kyusyu Kosei-Nenkin Hospital
Rumiko Matsuoka: Tokyo Women's Medical University
Jonathan C. Cohen: University of Texas Southwestern Medical Center at Dallas
Deepak Srivastava: University of Texas Southwestern Medical Center at Dallas

Nature, 2003, vol. 424, issue 6947, 443-447

Abstract: Abstract 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.

Date: 2003
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DOI: 10.1038/nature01827

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