title: Overlapping cardiac phenotype associated with a familial mutation in the voltage sensor of the KCNQ1 channel.
abstract: BACKGROUND
  Cardiac action potential repolarisation is determined by K(+) currents including I(Ks). I(Ks) channels are heteromeric channels composed of KCNQ1 and KCNE E-subunits. Mutations in KCNQ1 are associated with sinus bradycardia, familial atrial fibrillation (fAF) and/or short QT syndrome as a result of gain-of-function, and long QT syndrome (LQTS) due to loss-of-function in the ventricles. Here, we report that the missense mutation R231C located in S4 voltage sensor domain is associated with a combined clinical phenotype of sinus bradycardia, fAF and LQTS. We aim to understand the molecular basis of the complex clinical phenotype.
  
  
  METHODS
  We expressed and functionally analyzed the respective channels kinetics in Xenopus laevis oocytes. The molecular nature of the residue R231 was studied by homology modeling and molecular dynamics simulation.
  
  
  RESULTS
  As a result, the mutation reduced voltage sensitivity of channels, possibly due to neutralization of the positive charge of the arginine side chain substituted by cysteine. Modeling suggested that the charge carrying side chain of R231 is positioned suitably to transfer transmembrane voltages into conformational energy. Further, the mutation altered the functional interactions with KCNE subunits.
  
  
  CONCLUSIONS
  The mutation acted in a E-subunit dependent manner, suggesting I(Ks) function altered by the presence of different KCNE subunits in sinus node, atria and ventricles as the molecular basis of sinus bradycardia, fAF and LQTS in mutation carriers.
authors.affiliation: Biochemistry I - Cation Channel Group, Ruhr University Bochum, Bochum, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Henrion
authors.forename: Sven
authors.initials: S
authors.lastname: Zumhagen
authors.forename: Katja
authors.initials: K
authors.lastname: Steinke
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008297:Male; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human