A Novel GATA4 Loss-of-Function Mutation Associated With Congenital Ventricular Septal Defect

被引:0
作者
Yi-Qing Yang
Li Li
Juan Wang
Xing-Yuan Liu
Xiao-Zhong Chen
Wei Zhang
Xiao-Zhou Wang
Jin-Qi Jiang
Xu Liu
Wei-Yi Fang
机构
[1] Shanghai Chest Hospital,Department of Cardiovascular Research
[2] Medical College of Shanghai Jiaotong University,Key Laboratory of Arrhythmias, Ministry of Education
[3] Tongji University School of Medicine,Department of Cardiology
[4] East Hospital,Department of Pediatrics
[5] Tongji University School of Medicine,Department of Cardiac Surgery
[6] Tongji Hospital,Department of Pediatric Cardiac Surgery
[7] Tongji University School of Medicine,Department of Emergency
[8] Shanghai Chest Hospital,Department of Cardiology
[9] Medical College of Shanghai Jiaotong University,undefined
[10] Shanghai Chest Hospital,undefined
[11] Medical College of Shanghai Jiaotong University,undefined
[12] Shanghai Chest Hospital,undefined
[13] Medical College of Shanghai Jiaotong University,undefined
[14] Shanghai Chest Hospital,undefined
[15] Medical College of Shanghai Jiaotong University,undefined
来源
Pediatric Cardiology | 2012年 / 33卷
关键词
Genetics; Transcription factor; Ventricular septal defect;
D O I
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学科分类号
摘要
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.
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页码:539 / 546
页数:7
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