title: IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation.
abstract: BACKGROUND
  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.
  
  
  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 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 enhance the susceptibility to AF.
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Annette Buur
authors: AB
authors: Steffensen
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Lena
authors: L
authors: Refsgaard
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Martin Nybo
authors: MN
authors: Andersen
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Cecilia
authors: C
authors: Vallet
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Amer
authors: A
authors: Mujezinovic
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Stig
authors: S
authors: Haunsø
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Jesper Hastrup
authors: JH
authors: Svendsen
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Søren-Peter
authors: SP
authors: Olesen
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Morten Salling
authors: MS
authors: Olesen
authors: Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Nicole
authors: N
authors: Schmitt
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D016022:Case-Control Studies; D002460:Cell Line; D004252:DNA Mutational Analysis; D003718:Denmark; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006339:Heart Rate; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D011188:Potassium
keywords: cardiac arrhythmia; genetics; lone atrial fibrillation; molecular biology; potassium channel; trafficking; two-electrode voltage clamp