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, Deepak Srivastava

Research output: Contribution to journalArticlepeer-review

994 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)443-447
Number of pages5
Issue number6947
StatePublished - Jul 24 2003

ASJC Scopus subject areas

  • General


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