title: A novel GATA4 loss-of-function mutation associated with congenital ventricular septal defect.
abstract: Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and a major cause for the significantly increased morbidity and mortality among infants. Aggregating evidence indicates that genetic defects are involved in the pathogenesis of congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the genetic determinants for VSD in the majority of patients remain to be identified. In this study, the entire coding region of GATA4, a gene encoding a zinc finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 160 unrelated patients with VSD. The available relatives of the index patient harboring the identified mutation and 200 unrelated control individuals were subsequently genotyped. The disease-causing potential of a sequence alteration was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 variation, p.R43W, was identified in a proband with VSD, that was absent in control subjects. Genetic analysis of the family members of the variation carrier showed that the substitution co-segregated with VSD. The p.R43W variant was predicted to be a pathogenic mutation, and the functional analysis demonstrated that the GATA4 R43W mutant protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. The findings expand the mutational spectrum of GATA4 linked to VSD and provide more insight into the molecular mechanism of VSD.
authors.affiliation: Department of Cardiovascular Research, Shanghai Chest Hospital, Medical College of Shanghai Jiaotong University, 241 West Huaihai Road, Shanghai 200030, China. yang99yang66@hotmail.com
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Xing-Yuan
authors.initials: XY
authors.lastname: Liu
authors.forename: Xiao-Zhong
authors.initials: XZ
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiao-Zhou
authors.initials: XZ
authors.lastname: Wang
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
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006345:Heart Septal Defects, Ventricular / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis
chemical_list: D050991:GATA4 Transcription Factor; D004247:DNA
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