title: Gain-of-function mutations in GATA6 lead to atrial fibrillation.
abstract: The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood.
  
  
  
  We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects.
  
  
  
  We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early-onset AF was prominent in the family, we then screened individuals with early-onset AF, defined as an age of onset <66 years, for mutations in GATA6. Variants were functionally characterized using reporter assays in a mammalian cell line.
  
  
  
  Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6. In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 ± 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P < .0001; P91S: 2.5-fold, P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity.
  
  
  
  Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early-onset AF.
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Tucker
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Saagar
authors.initials: S
authors.lastname: Mahida
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Jiangchuan
authors.initials: J
authors.lastname: Ye
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Abraham
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mina
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Parsons
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McLellan
authors.affiliation: Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Marisa A
authors.initials: MA
authors.lastname: Shea
authors.affiliation: Cardiovascular Research Center and.
authors.forename: Alan
authors.initials: A
authors.lastname: Hanley
authors.affiliation: National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts; Preventive Medicine and Cardiovascular Medicine Sections, Department of Medicine; Cardiology Division, Department of Medicine.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Cardiovascular Research Center and; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Milan
authors.affiliation: Computational Biomedicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Cardiovascular Research Center and; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: ellinor@mgh.harvard.edu.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
mesh_terms: D000328:Adult; D017668:Age of Onset; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics*; D006344:Heart Septal Defects, Atrial / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D006345:Heart Septal Defects, Ventricular / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human
keywords: Atrial fibrillation; Genetics; Mutation; Transcription factor