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Heart Rhythm. 2014 Jun;11(6):1055-62. doi: 10.1016/j.hrthm.2014.03.002. Epub 2014 Mar 4.

A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation.

Author information

  • 1Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Harvard Medical School, Boston, Massachusetts.
  • 2Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts.
  • 3Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts.
  • 4Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
  • 5National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
  • 6National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts; Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; Cardiology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 7Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Harvard Medical School, Boston, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: ellinor@mgh.harvard.edu.

Abstract

BACKGROUND:

Atrial fibrillation (AF) is the most common arrhythmia, and a recent genome-wide association study identified the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) as a novel AF susceptibility locus. HCN4 encodes for the cardiac pacemaker channel, and HCN4 mutations are associated with familial sinus bradycardia and AF.

OBJECTIVE:

The purpose of this study was to determine whether novel variants in the coding region of HCN4 contribute to the susceptibility for AF.

METHODS:

We sequenced the coding region of HCN4 for novel variants from 527 cases with early-onset AF from the Massachusetts General Hospital AF Study and 443 referents from the Framingham Heart Study. We used site-directed mutagenesis, cellular electrophysiology, immunocytochemistry, and confocal microscopy to functionally characterize novel variants.

RESULTS:

We found the frequency of novel coding HCN4 variants was 2-fold greater for individuals with AF (7 variants) compared to the referents (3 variants). We determined that of the 7 novel HCN4 variants in our AF cases, 1 (p.Pro257Ser, located in the amino-terminus adjacent to the first transmembrane spanning domain) did not traffic to cell membrane, whereas the remaining 6 were not functionally different from wild type. In addition, the 3 novel variants in our referents did not alter function compared to wild-type. Coexpression studies showed that the p.Pro257Ser mutant channel failed to colocalize with the wild-type HCN4 channel on the cell membrane.

CONCLUSION:

Our findings are consistent with HCN4 haploinsufficiency as the likely mechanism for early-onset AF in the p.Pro257Ser carrier.

Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Atrial fibrillation; Electrophysiology; HCN4; Mutation

PMID:
24607718
[PubMed - in process]
PMCID:
PMC4130372
[Available on 2015/6/1]
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