title: Novel GATA6 loss-of-function mutation responsible for familial atrial             fibrillation.
abstract: Atrial fibrillation (AF) is the most commonly sustained cardiac arrhythmia, and confers a substantially increased risk of morbidity and mortality. Increasing evidence has indicated that hereditary defects are implicated in AF. However, AF is genetically heterogeneous and the genetic etiology of AF in a significant portion of patients remains unclear. In this study, the entire coding sequence and splice junctions of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, were sequenced in 140 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as the controls were genotyped. The functional characteristics of the mutant GATA6 were assessed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.G469V, was identified in a family with AF inherited in an autosomal dominant pattern. The mutation was absent in the 200 control individuals and the altered amino acid was completely conserved across species. Functional analysis demonstrated that the GATA6 mutation was associated with a significantly decreased transcriptional activity. The findings provide novel insight into the molecular mechanism involved in the pathogenesis of AF, as well as insight into potential therapies for the prevention and treatment of AF.
authors: Department of Emergency, Pu Nan Hospital, Shanghai 200125, PR China.
authors: Jian
authors: J
authors: Li
authors: Wei-Dong
authors: WD
authors: Liu
authors: Zhong-Liang
authors: ZL
authors: Yang
authors: Yi-Qing
authors: YQ
authors: Yang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D001281:Atrial Fibrillation / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D050993:GATA6 Transcription Factor / Q000737:chemistry / Q000235:genetics*; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016415:Sequence Alignment; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human