title: Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation.
abstract: OBJECTIVE
  The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF).
  
  
  METHODS
  A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system.
  
  
  RESULTS
  Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart.
  
  
  CONCLUSIONS
  These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia.
authors.affiliation: Shanghai Jiao Tong University School of Medicine, Shanghai Chest Hospital, Department of Nuclear Medicine, Shanghai 200030, China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Xie
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000595:Amino Acid Sequence; D001281:Atrial Fibrillation / Q000235:genetics*; D016022:Case-Control Studies; D005190:Family; D005260:Female; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors; D008156:Luciferases