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XB-ART-5031
Nature. July 24, 2003; 424 (6947): 443-7.

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

Garg V , Kathiriya IS , Barnes R , Schluterman MK , King IN , Butler CA , Rothrock CR , Eapen RS , Hirayama-Yamada K , Joo K , Matsuoka R , Cohen JC , Srivastava D .


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.

PubMed ID: 12845333
Article link: Nature.
Grant support: L40 HL078465-02 NHLBI NIH HHS , L40 HL078465 NHLBI NIH HHS

Genes referenced: gata4 nkx2-5 tbx5



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