title: GATA4 loss-of-function mutations in familial atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of the substantially increased morbidity and mortality. Growing studies demonstrate that genetic defects play pivotal roles in a subgroup of AF. However, AF is a genetically heterogeneous disorder and the molecular basis of AF in a majority of cases remains unknown.
  
  
  METHODS
  The whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was analyzed in 130 unrelated probands with AF in contrast to 200 unrelated ethnically matched healthy individuals used as controls. The available family members of the probands harboring the identified mutations were genotyped. The functional effect of the mutant GATA4 was characterized using a luciferase reporter assay system.
  
  
  RESULTS
  Two novel heterozygous GATA4 mutations, p.S70T and p.S160T, were identified in 2 unrelated families with AF inherited as an autosomal dominant trait, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis showed that the mutations of GATA4 were associated with a significantly decreased transcriptional activity.
  
  
  CONCLUSIONS
  The findings provide new insight into the molecular mechanism involved in the pathogenesis of AF, suggesting the potential implications in the genetic diagnosis and gene-specific therapy of this common arrhythmia.
authors.affiliation: Department of Cardiovascular Research, Shanghai Chest Hospital, Medical College of Shanghai Jiaotong University, PR China. yang99yang66@hotmail.com
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
authors.forename: Mao-Ya
authors.initials: MY
authors.lastname: Wang
authors.forename: Xian-Ling
authors.initials: XL
authors.lastname: Zhang
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Tan
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Shi
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Jiang
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Wang
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D001483:Base Sequence; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D017931:DNA Primers; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D017930:Genes, Reporter; D006579:Heterozygote; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D017931:DNA Primers; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D008156:Luciferases