title: A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy.
abstract: Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 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 characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, 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 revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001, P.R. China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Jin-Fa
authors.initials: JF
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D022821:RNA Splice Sites