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

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• 作者：Nathan R. Tucker ; PhD^* ; Saagar Mahida ; MB ; ChB^* ; Jiangchuan Ye ; MD ; PhD^* ; Elizabeth J. Abraham ; BS^* ; Julie A. Mina ; BS^* ; Victoria A. Parsons ; BS^* ; Michael A. McLellan ; BS^* ; Marisa A. Shea ; BS ; RN^&dagger ; ; Alan Hanley ; MD^* ; Emelia J. Benjamin ; MD ; MSc^&Dagger ; ; ^§ ; ; ^║ ; David J. Milan ; MD^* ; ^&dagger ; ; Honghuang Lin ; PhD^¶ ; ; Patrick T. Ellinor ; MD ; PhD^* ; ^&dagger ; ; ^{ellinor@mgh.harvard.edu}
• 关键词：Atrial fibrillation ; Mutation ; Transcription factor ; Genetics
• 刊名：Heart Rhythm
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：14
• 期：2
• 页码：284-291
• 全文大小：461 K
• 卷排序：14

文摘

The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood.ObjectiveWe sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects.MethodsWe 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.ResultsExome 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.ConclusionOverall, 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.