title: GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy.
abstract: The cardiac transcription factor GATA4 is essential for cardiac development, and mutations in this gene have been implicated in a wide variety of congenital heart diseases in both animal models and humans. However, whether mutated GATA4 predisposes to dilated cardiomyopathy (DCM) remains unknown. In this study, the whole coding region and splice junction sites of the GATA4 gene was sequenced in 110 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.C271S, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis demonstrated that the GATA4 mutant was associated with significantly decreased transcriptional activity and remarkably reduced synergistic activation between GATA4 and NKX2-5, another transcription factor crucial for cardiogenesis. The findings provide novel insight into the molecular mechanisms involved in the pathogenesis of DCM, suggesting the potential implications in the prenatal diagnosis and gene-specific treatment for this common form of myocardial disorder.
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Jiang
authors.forename: Jin-Qi
authors.initials: JQ
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Lu-Ying
authors.initials: LY
authors.lastname: Peng
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors
keywords: Dilated cardiomyopathy; GATA4; Genetics; NKX2-5; Transcription factor