In:
Journal of Cardiovascular Electrophysiology, Wiley, Vol. 26, No. 7 ( 2015-07), p. 715-723
Abstract:
Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current I Ks is essential for cardiac repolarization. Gain‐of‐function mutation in KCNQ1 , the gene encoding the pore‐forming α‐subunit of the I Ks channel (K V 7.1), was the first ion channel dysfunction to be associated with familial AF. We hypothesized that early‐onset lone AF is associated with a high prevalence of mutations in KCNQ1 . Methods and Results We bidirectionally sequenced the entire coding sequence of KCNQ1 in 209 unrelated patients with early‐onset lone AF ( 〈 40 years) and investigated the identified mutations functionally in a heterologous expression system. We found 4 nonsynonymous KCNQ1 mutations (A46T, R195W, A302V, and R670K) in 4 unrelated patients (38, 31, 39, and 36 years, respectively). None of the mutations were present in the control group (n = 416 alleles). No other mutations were found in genes previously associated with AF. The mutations A46T, R195W, and A302V have previously been associated with long‐QT syndrome. In line with previous reports, we found A302V to display a pronounced loss‐of‐function of the I Ks current, while the other mutants exhibited a gain‐of‐function phenotype. Conclusions Mutations in the I Ks channel leading to gain‐of‐function have previously been described in familial AF, yet this is the first time a loss‐of‐function mutation in KCNQ1 is associated with early‐onset lone AF. These findings suggest that both gain‐of‐function and loss‐of‐function of cardiac potassium currents enhance the susceptibility to AF.
Type of Medium:
Online Resource
ISSN:
1045-3873
,
1540-8167
DOI:
10.1111/jce.2015.26.issue-7
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2037519-0
