title: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.
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.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Rm. NA8.124, Dallas, Texas 75390-9148, USA. Vidu.Garg@UTSouthwestern.edu
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
authors.forename: Irfan S
authors.initials: IS
authors.lastname: Kathiriya
authors.forename: Robert
authors.initials: R
authors.lastname: Barnes
authors.forename: Marie K
authors.initials: MK
authors.lastname: Schluterman
authors.forename: Isabelle N
authors.initials: IN
authors.lastname: King
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Butler
authors.forename: Caryn R
authors.initials: CR
authors.lastname: Rothrock
authors.forename: Reenu S
authors.initials: RS
authors.lastname: Eapen
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hirayama-Yamada
authors.forename: Kunitaka
authors.initials: K
authors.lastname: Joo
authors.forename: Rumiko
authors.initials: R
authors.lastname: Matsuoka
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D050991:GATA4 Transcription Factor; D006367:HeLa Cells; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011233:Precipitin Tests; D011485:Protein Binding; D020825:T-Box Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D029867:Xenopus Proteins
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D029867:Xenopus Proteins; D004247:DNA