1. Academic Validation
  2. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5

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

  • Nature. 2003 Jul 24;424(6947):443-7. doi: 10.1038/nature01827.
Vidu Garg 1 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 Deepak Srivastava
Affiliations

Affiliation

  • 1 Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Rm. NA8.124, Dallas, Texas 75390-9148, USA. [email protected]
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.

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