title: Stretch-sensitive KCNQ1 mutation A link between genetic and environmental factors in the pathogenesis of atrial fibrillation?
abstract: OBJECTIVE
  This study sought to evaluate mutations in genes encoding the slow component of the cardiac delayed rectifier K+ current (I(Ks)) channel in familial atrial fibrillation (AF).
  
  
  BACKGROUND
  Although AF can have a genetic etiology, links between inherited gene defects and acquired factors such as atrial stretch have not been explored.
  
  
  METHODS
  Mutation screening of the KCNQ1, KCNE1, KCNE2, and KCNE3 genes was performed in 50 families with AF. The effects of mutant protein on cardiac I(Ks) activation were evaluated using electrophysiological studies and human atrial action potential modeling.
  
  
  RESULTS
  One missense KCNQ1 mutation, R14C, was identified in 1 family with a high prevalence of hypertension. Atrial fibrillation was present only in older individuals who had developed atrial dilation and who were genotype positive. Patch-clamp studies of wild-type or R14C KCNQ1 expressed with KCNE1 in CHO cells showed no statistically significant differences between wild-type and mutant channel kinetics at baseline, or after activation of adenylate cyclase with forskolin. After exposure to hypotonic solution to elicit cell swelling/stretch, mutant channels showed a marked increase in current, a leftward shift in the voltage dependence of activation, altered channel kinetics, and shortening of the modeled atrial action potential duration.
  
  
  CONCLUSIONS
  These data suggest that the R14C KCNQ1 mutation alone is insufficient to cause AF. Rather, we suggest a model in which a "second hit", such as an environmental factor like hypertension, which promotes atrial stretch and thereby unmasks an inherited defect in ion channel kinetics (the "first hit"), is required for AF to be manifested. Such a model would also account for the age-related increase in AF development.
authors.affiliation: Sr. Bernice Research Program in Inherited Heart Diseases, Darlinghurst, New South Wales, Australia.
authors.forename: Robyn
authors.initials: R
authors.lastname: Otway
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.forename: Guanglan
authors.initials: G
authors.lastname: Guo
authors.forename: Anthony
authors.initials: A
authors.lastname: Varghese
authors.forename: M Leticia
authors.initials: ML
authors.lastname: Castro
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: JingTing
authors.initials: J
authors.lastname: Zhao
authors.forename: Jane A
authors.initials: JA
authors.lastname: Bursill
authors.forename: Ken R
authors.initials: KR
authors.lastname: Wyse
authors.forename: Haley
authors.initials: H
authors.lastname: Crotty
authors.forename: Olivia
authors.initials: O
authors.lastname: Baddeley
authors.forename: Bruce
authors.initials: B
authors.lastname: Walker
authors.forename: Dennis
authors.initials: D
authors.lastname: Kuchar
authors.forename: Charles
authors.initials: C
authors.lastname: Thorburn
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D006325:Heart Atria / Q000503:physiopathology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated