title: The Mutation P.T613a in the Pore Helix of the Kv 11.1 Potassium Channel is Associated with Long QT Syndrome.
abstract: BACKGROUND
  Loss-of-function mutations in the voltage gated potassium channel Kv 11.1 have been associated with the Long QT Syndrome (LQTS) type 2. We identified the p.T613A mutation in Kv 11.1 in a family with LQTS. T613A is located in the outer part of the pore helix, a structure that is involved in C-type inactivation. Here we characterize the effect of p.T613A on the functional properties of KV 11.1.
  
  
  METHODS
  The p.T613A mutation was introduced into KV 11.1 (T613A). Wild-type KV 11.1 (WT) and T613A were expressed in Xenopus laevis oocytes and characterized by two-electrode-voltage-clamp.
  
  
  RESULTS
  T613A currents were reduced to <20% of WT currents and T613A induced a minor negative shift in half maximal rectification, indicating that the voltage-dependent onset on inactivation occurred at more negative voltages compared to WT. Co-expression of T613A with WT revealed intermediate phenotype and there was no dominant negative effect of T613A.
  
  
  CONCLUSIONS
  These findings suggest that p.T613A causes a loss-of-function of Kv 11.1. This results in a reduced repolarizing reserve which may result in LQTS2 and sudden cardiac death.
authors.affiliation: Department of Veterinary Clinical and Animal Science, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Kristian L
authors.initials: KL
authors.lastname: Poulsen
authors.affiliation: Cardiology Division, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Hotait
authors.affiliation: Department of Veterinary Clinical and Animal Science, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.affiliation: Department of Veterinary Clinical and Animal Science, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Klaerke
authors.affiliation: Cardiology Division, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Rebeiz
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: Georges
authors.initials: G
authors.lastname: Nemer
authors.affiliation: Department of Veterinary Clinical and Animal Science, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Tejada
authors.affiliation: Cardiology Division, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.|Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: Marwan M
authors.initials: MM
authors.lastname: Refaat
mesh_terms: D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel / Q000235:genetics*; D017809:Fatal Outcome; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D015221:Potassium Channels
keywords: HERG; KV11.1; LQTS; sudden cardiac death