BACKGROUND: Atrial Fibrillation (AF) is the most common cardiac arrhythmia, affecting over 3 million Americans. Many people who suffer from AF have pre-disposing factors such as hypertension, ischemia, and structural heart disease, but recent research has also demonstrated the importance of genetic factors that can contribute to AF. In the present study, we sought to determine the causative mutation in a family with AF, atrial septal, and ventricular septal defects.
METHODS: We evaluated a pedigree with 16 family members, one of whom had an ASD, one a VSD, and three had AF. Exome sequencing was performed on three of the five affected family members followed by confirmation with Sanger sequencing in all family members. A separate cohort from the MGH AF Study with early-onset AF (age at onset 47.1 ± 10.9 years, 79.3% male) was also screened for mutations using a combination of Sanger sequencing and high resolution melting. Variants were then functionally characterized using reporter assays in a mammalian cell line using wild-type and mutant constructs driving NPPA, αMHC and NPPB promoter reporters.
RESULTS: Exome sequencing of the three affected individuals in the family identified a highly conserved mutation, R585L, in the transcription factor gene, GATA6. We also identified three additional GATA6 variants (P91S, A177T, and A543G) in the cases with early-onset AF from the MGH AF Study. We found that three of the four variants had a marked upregulation of luciferase activity (R585L; 4.1 fold, p<0.0001; P91S; 2.5 fold, p=0.0002; A177T; 1.7 fold, p=0.03). Additionally, when co-overexpressed with GATA4 and MEF2C, all GATA6 variants exhibited upregulation of the αMHC and NPPA activity compared to control.
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 patients with sporadic, early-onset AF. This evidence suggests that specific gain of function mutations in GATA6 contribute to the development of AF. / 2017-06-16T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/16744 |
| Date | 16 June 2016 |
| Creators | Abraham, Elizabeth June |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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