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Heart Rhythm. 2017 Feb;14(2):284-291. doi: 10.1016/j.hrthm.2016.10.014. Epub 2016 Oct 15.

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

Author information

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.

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

PMID:
27756709
DOI:
10.1016/j.hrthm.2016.10.014
[Indexed for MEDLINE]

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