KCNQ1 mutation Q147R is associated with atrial fibrillation and prolonged QT interval Alicia Lundby, MSc,* 1 Lasse Steen Ravn, MD, †1 Jesper Hastrup Svendsen, MD, † Søren-Peter Olesen, MD, PhD,* Nicole Schmitt, PhD* From the *Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark, and † Danish National Research Foundation Centre for Cardiac Arrhythmia, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark. BACKGROUND Atrial fibrillation (AF) and long QT syndrome (LQTS) are cardiac arrhythmia disorders that have been related to dysfunction of the voltage-gated potassium channel subunit Kv7.1 encoded by the KCNQ1 gene. OBJECTIVE The purpose of this study was functional assessment of a mutation in Kv7.1 identified in a proband with permanent AF and prolonged QT interval. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and LQTS simultaneously in this patient. METHODS We investigated the functional consequences of the novel mutation KCNQ1 Q147R by heterologous expression of the channel and accessory subunits in Xenopus laevis oocytes and mammalian cells. RESULTS The Q147R mutation does not affect the biophysical properties of Kv7.1 in the absence of accessory subunits. Upon coexpression with the -subunit KCNE1, the Q147R mutation in- duced a loss of function, observed as a decrease in current am- plitude at depolarized potentials. Additionally, Q147R abolished the frequency dependence of charge carried by Kv7.1/KCNE1 chan- nels. Coexpression with the -subunit KCNE2 revealed a gain of function for the mutant, seen as an increase in the current am- plitude at depolarized potentials. The properties of channels formed by Kv7.1 and the subunits KCNE3 and KCNE4 were unaf- fected by the Q147R mutation. CONCLUSION Our data indicate that the Q147R mutation can form the molecular substrate simultaneously for different arrhyth- mogenic conditions. The mechanism may be heterogeneous dis- tribution of Kv7.1 accessory subunits in the heart leading to Kv7.1 gain of function in the atria (for AF) and Kv7.1 loss of function in the ventricles (for QT prolongation). KEYWORDS Arrhythmia; Atrial fibrillation; QT interval; Potassium channel; Kv7.1; KCNQ1; KCNE1; KCNE2; Two-electrode voltage clamp (Heart Rhythm 2007;4:1532–1541) © 2007 Heart Rhythm Society. All rights reserved. Introduction Atrial fibrillation (AF) is the most common cardiac arrhyth- mia occurring in the general population. AF is characterized by rapid irregular atrial activation. In rare cases, AF occurs in clusters in families 1 and shows some degree of heritabil- ity. 2 Its prevalence increases with age; currently AF affects more than 5% of the western population older than 65 years. 3 AF is a potentially serious disease, primarily be- cause of thromboembolic complications and heart failure. 4 Genetic linkage analyses have identified several loci on various chromosomes associated with AF. 5–12 The genetic defect has been identified in five cases as missense mutations in KCNQ1, KCNE2, KCNJ2, KCNH2, and KCNA5. Interest- ingly, the genes identified encode cardiac potassium chan- nel subunits. In addition, variations in the KCNE5 and SCN5A genes have been associated with AF, the latter encoding the cardiac sodium channel Na v 1.5. 13–15 Other cases of familial AF demonstrate no linkage between the disease and these loci, 16 indicating that other genetic heter- ogeneity is to be expected. Long QT syndrome (LQTS) is a genetically heteroge- nous cardiac disease characterized by prolonged ventricular repolarization. Affected individuals are at high risk for the ventricular tachyarrhythmia Torsade de Pointes, loss of consciousness, and, in the worst cases, sudden cardiac death (for review see Schwartz 17 ). The surface ECG of an affected patient shows a prolonged corrected QT interval (QTc) and abnormal T-wave morphology. However, various clinical signs of life-threatening cardiac arrhythmias are required to confirm the diagnosis. 18 A QTc interval 440 ms is con- sidered prolonged. In the absence of other clinical signs of LQTS, a patient with QTc interval ranging from 450 to 470 1 The first two authors contributed equally to this work. The work was supported by the Danish National Research Foundation to Dr. Schmitt and the Birthe and John Meyer Foundation to Dr. Svendsen. A. Lundby and Dr. Ravn received research fellowships from the Danish Cardiovascular Research Academy (DaCRA). Address reprint requests and correspondence: Dr. Nicole Schmitt, The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail address: nschmitt@mfi.ku.dk. (Received January 2, 2007; accepted July 21, 2007.) 1547-5271/$ -see front matter © 2007 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2007.07.022