title: A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation.
abstract: OBJECTIVE
  Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current (Ito) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K(+) Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF.
  
  
  RESULTS
  Two hundred and nine unrelated early-onset lone AF patients (<40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group (n = 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of KV4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2.
  
  
  CONCLUSIONS
  Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early-onset lone AF. This association of KV4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.
authors: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark. morten.salling.olesen@rh.regionh.dk
authors: Morten Salling
authors: MS
authors: Olesen
authors: Lena
authors: L
authors: Refsgaard
authors: Anders Gaarsdal
authors: AG
authors: Holst
authors: Anders Peter
authors: AP
authors: Larsen
authors: Søren
authors: S
authors: Grubb
authors: Stig
authors: S
authors: Haunsø
authors: Jesper Hastrup
authors: JH
authors: Svendsen
authors: Søren-Peter
authors: SP
authors: Olesen
authors: Nicole
authors: N
authors: Schmitt
authors: Kirstine
authors: K
authors: Calloe
mesh_terms: D000328:Adult; D017668:Age of Onset; D000818:Animals; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D016466:CHO Cells; D016022:Case-Control Studies; D006224:Cricetinae; D003412:Cricetulus; D003718:Denmark; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000235:genetics; D008297:Male; D008564:Membrane Potentials; D009154:Mutation; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D051672:Shal Potassium Channels / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: C497021:KCND3 protein, human; C496752:KCNIP2 protein, human; D051605:Kv Channel-Interacting Proteins; D051672:Shal Potassium Channels; D011188:Potassium
keywords: Atrial fibrillation; Brugada syndrome; KCND3; KCNIP2; KV4.3; Transient outward potassium current