title: A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.
abstract: OBJECTIVE
  KCNQ1 and KCNE1 encode Kv7.1 and KCNE1, respectively, the pore-forming and the accessory subunits of the slow delayed rectifier potassium current, IKs. KCNQ1 mutations are associated with long and short QT syndrome. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNQ1 missense mutation, F279I, found in a 23-year-old man with a corrected QT interval (QTc) of 356 ms and a family history of sudden cardiac death.
  
  
  RESULTS
  Experiments were performed using perforated patch-clamp, western blot, co-immunoprecipitation, biotinylation, and immunocytochemistry techniques in HEK293, COS7 cells and in cardiomyocytes transfected with WT Kv7.1/KCNE1 or F279I Kv7.1/KCNE1 channels. In the absence of KCNE1, F279I Kv7.1 current exhibited a lesser degree of inactivation than WT Kv7.1. Also, functional analysis of F279I Kv7.1 in the presence of KCNE1 revealed a negative shift in the activation curve and an acceleration of the activation kinetics leading to a gain of function in IKs. The co-assembly between F279I Kv7.1 channels and KCNE1 was markedly decreased compared with WT Kv7.1 channels, as revealed by co-immunoprecipitation and Föster Resonance Energy Transfer experiments. All these effects contribute to the increase of IKs when channels incorporate F279I Kv7.1 subunits, as shown by a computer model simulation of these data that predicts a shortening of the action potential (AP) consistent with the patient phenotype.
  
  
  CONCLUSIONS
  The F279I mutation induces a gain of function of IKs due to an impaired gating modulation of Kv7.1 induced by KCNE1, leading to a shortening of the cardiac AP.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, C/Arturo Duperier 4, Madrid 28029, Spain cvalenzuela@iib.uam.es c.moreno@maastrichtuniversity.nl.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Oliveras
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, C/Arturo Duperier 4, Madrid 28029, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: de la Cruz
authors.affiliation: Cellular and Molecular Engineering Laboratory 'S. Cavalcanti', Department of Electrical, Electronic and Information Engineering 'Guglielmo Marconi', University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bartolucci
authors.affiliation: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca de Murcia, Murcia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Muñoz
authors.affiliation: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca de Murcia, Murcia, Spain.
authors.forename: Eladia
authors.initials: E
authors.lastname: Salar
authors.affiliation: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca de Murcia, Murcia, Spain.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Gimeno
authors.affiliation: Cellular and Molecular Engineering Laboratory 'S. Cavalcanti', Department of Electrical, Electronic and Information Engineering 'Guglielmo Marconi', University of Bologna, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Severi
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Comes
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Felipe
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, C/Arturo Duperier 4, Madrid 28029, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: González
authors.affiliation: Department of Cardiac Electrophysiology, The Heart Hospital, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Pier
authors.initials: P
authors.lastname: Lambiase
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, C/Arturo Duperier 4, Madrid 28029, Spain cvalenzuela@iib.uam.es c.moreno@maastrichtuniversity.nl.
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
mesh_terms: D000200:Action Potentials; D057809:HEK293 Cells; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*
chemical_list: C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated
keywords: Electrophysiology; FRET; KCNE1; Kv7.1; Short QT syndrome