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. Epub 2003 Jul 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Chromosome Mapping
  • Chromosomes, Human, Pair 8 / genetics
  • DNA / genetics
  • DNA / metabolism
  • DNA Mutational Analysis
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Female
  • Frameshift Mutation / genetics
  • GATA4 Transcription Factor
  • HeLa Cells
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / physiopathology
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mutation / genetics*
  • Pedigree
  • Precipitin Tests
  • Protein Binding
  • T-Box Domain Proteins / chemistry
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Xenopus Proteins*

Substances

  • DNA-Binding Proteins
  • GATA4 Transcription Factor
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • NKX2-5 protein, human
  • Nkx2-5 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Transcription Factors
  • Xenopus Proteins
  • DNA