title: A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation.
abstract: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia,             is associated with significantly increased morbidity and mortality. Cumulative             evidence highlights the importance of genetic defects in the pathogenesis of AF.             However, AF is of remarkable heterogeneity and the genetic determinants of AF             in a vast majority of patients remain illusive. In this study, the coding exons             and splice junctions of the GATA5 gene, which encodes a zinc-finger transcription             factor essential for normal cardiogenesis, were sequenced in 118 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 controls             were genotyped. The functional effect of the mutant GATA5 was characterized in             contrast to its wild-type counterpart using a luciferase reporter assay system.             As a result, a novel heterozygous GATA5 mutation, p.W200G, was identified in a             family with AF inherited as an autosomal dominant trait. The mutation was absent             in 200 control individuals and the altered amino acid was completely conserved             evolutionarily across species. Functional analysis showed that the mutation of             GATA5 was associated with a significantly decreased transcriptional activity.             These findings provide novel insight into the molecular mechanism involved in             AF, suggesting potential implications for the early prophylaxis and gene-specific             therapy of AF.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Wang
authors.forename: Cong-Xin
authors.initials: CX
authors.lastname: Huang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology*; D016022:Case-Control Studies; D002681:China; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D017930:Genes, Reporter; D015316:Genetic Therapy; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment
chemical_list: D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human; D008156:Luciferases