TY - JOUR

T1 - IKs Gain- and Loss-of-Function In Early-Onset Lone Atrial Fibrillation

AU - Steffensen, Annette Buur

AU - Refsgaard, Lena

AU - Andersen, Martin Nybo

AU - Vallet, Cecilia

AU - Mujezinovic, Amer

AU - Haunsø, Stig

AU - Svendsen, Jesper Hastrup

AU - Olesen, Søren-Peter

AU - Olesen, Morten Salling

AU - Schmitt, Nicole

N1 - This article is protected by copyright. All rights reserved.

PY - 2015

Y1 - 2015

N2 - INTRODUCTION: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutation in KCNQ1, the gene encoding the pore-forming α-subunit of the IKs channel (KV 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 four non-synonymous 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 IKs current, while the other mutants exhibited a gain-of-function phenotype.CONCLUSIONS: Mutations in the IKs 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 enhances the susceptibility to AF. This article is protected by copyright. All rights reserved.

AB - INTRODUCTION: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutation in KCNQ1, the gene encoding the pore-forming α-subunit of the IKs channel (KV 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 four non-synonymous 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 IKs current, while the other mutants exhibited a gain-of-function phenotype.CONCLUSIONS: Mutations in the IKs 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 enhances the susceptibility to AF. This article is protected by copyright. All rights reserved.

U2 - 10.1111/jce.12666

DO - 10.1111/jce.12666

M3 - Journal article

C2 - 25786344

VL - 26

SP - 715

EP - 723

JO - Journal of Cardiovascular Electrophysiology

JF - Journal of Cardiovascular Electrophysiology

SN - 1045-3873

IS - 7

ER -