title: Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation.
abstract: OBJECTIVE
  Genetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel α-subunit KV1.5, which underlies the voltage-gated atrial-specific potassium current IKur. KCNAB2 encodes KVβ2, a β-subunit of KV1.5, which increases IKur. Three studies have identified loss-of-function mutations in KCNA5 in patients with idiopathic AF. We hypothesized that early-onset lone AF is associated with high prevalence of genetic variants in KCNA5 and KCNAB2.
  
  
  RESULTS
  The coding sequences of KCNA5 and KCNAB2 were sequenced in 307 patients with mean age of 33 years at the onset of lone AF, and in 216 healthy controls. We identified six novel non-synonymous mutations [E48G, Y155C, A305T (twice), D322H, D469E, and P488S] in KCNA5 in seven patients. None were present in controls. We identified a significantly higher frequency of rare deleterious variants in KCNA5 in the patients than in controls. The mutations were analysed with confocal microscopy and whole-cell patch-clamp techniques. The mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for KV1.5.
  
  
  CONCLUSIONS
  This study is the first to present gain-of-function mutations in KCNA5 in patients with early-onset lone AF. We identified three gain-of-function and three loss-of-function mutations. We report a high prevalence of variants in KCNA5 in these patients. This supports the hypothesis that both increased and decreased potassium currents enhance AF susceptibility.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, Denmark.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Christophersen
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.forename: Martin N
authors.initials: MN
authors.lastname: Andersen
authors.forename: Anders P
authors.initials: AP
authors.lastname: Larsen
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Nielsen
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Arnljot
authors.initials: A
authors.lastname: Tveit
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000704:Analysis of Variance; D001281:Atrial Fibrillation / Q000235:genetics*; D005260:Female; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D051637:Shaker Superfamily of Potassium Channels
chemical_list: C496981:KCNA5 protein, human; C498948:KCNAB2 protein, human; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D051637:Shaker Superfamily of Potassium Channels