title: A Novel Missense Mutation of GATA4 in a Chinese Family with Congenital Heart Disease.
abstract: BACKGROUND
  Congenital heart disease (CHD) is the most prevalent type of birth defect in human, with high morbidity in infant. Several genes essential for heart development have been identified. GATA4 is a pivotal transcription factor that can regulate the cardiac development. Many GATA4 mutations have been identified in patients with different types of CHD.
  
  
  OBJECTIVE
  In this study, the NKX2-5, HAND1 and GATA4 coding regions were sequenced in a family spanning three generations in which seven patients had CHD. Disease-causing potential variation in this family was evaluated by bioinformatics programs and the transcriptional activity of mutant protein was analyzed by the dual luciferase reporter assay.
  
  
  RESULTS
  A novel GATA4 mutation, c.C931T (p.R311W), was identified and co-segregated with the affected patients in this family. The bioinformatics programs predicted this heterozygous mutation to be deleterious and the cross-species alignment of GATA4 sequences showed that the mutation occurred within a highly conserved amino acid. Even though it resided in the nuclear localization signal domain, the mutant protein didn't alter its intracellular distribution. Nevertheless, further luciferase reporter assay demonstrated that the p.R311W mutation reduced the ability of GATA4 to activate its downstream target gene.
  
  
  CONCLUSIONS
  Our study identified a novel mutation in GATA4 that likely contributed to the CHD in this family. This finding expanded the spectrum of GATA4 mutations and underscored the pathogenic correlation between GATA4 mutations and CHD.
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoqing
authors.identifier: http://orcid.org/0000-0002-2106-2994
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Sun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
mesh_terms: D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D005190:Family; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; C484170:GATA4 protein, human; C095552:NKX2-5 protein, human; C097341:helix-loop-helix protein, eHAND