2. Academic Validation
  3. Gain-of-function mutations in GATA6 lead to atrial fibrillation

Gain-of-function mutations in GATA6 lead to atrial fibrillation

  • Heart Rhythm. 2017 Feb;14(2):284-291. doi: 10.1016/j.hrthm.2016.10.014.
Nathan R Tucker 1,  Saagar Mahida 1,  Jiangchuan Ye 1,  Elizabeth J Abraham 1,  Julie A Mina 1,  Victoria A Parsons 1,  Michael A McLellan 1,  Marisa A Shea 2,  Alan Hanley 1,  Emelia J Benjamin 3,  David J Milan 4,  Honghuang Lin 5,  Patrick T Ellinor 6
Affiliations

Affiliations

  • 1 Cardiovascular Research Center and.
  • 2 Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
  • 3 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.
  • 4 Cardiovascular Research Center and; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
  • 5 Computational Biomedicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 6 Cardiovascular Research Center and; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: ellinor@mgh.harvard.edu.
PMID: 27756709 DOI: 10.1016/j.hrthm.2016.10.014
Abstract

Background: The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood.

Objective: We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords

Atrial fibrillation; Genetics; Mutation; Transcription factor.

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