title: A dual mechanism for I(Ks) current reduction by the pathogenic mutation KCNQ1-S277L.
abstract: BACKGROUND
  The hereditary long QT syndrome is characterized by prolonged ventricular repolarization that can be caused by mutations to the KCNQ1 gene, which encodes the α subunits of the cardiac potassium channel complex that carries the I(Ks) current (the β subunits are encoded by KCNE1). In this study, we characterized a deleterious variant, KCNQ1-S277L, found in a patient who presented with sudden cardiac death in the presence of cocaine use.
  
  
  METHODS
  The KCNQ1-S277L mutation was analyzed via whole-cell patch clamp, confocal imaging, surface biotinylation assays, and computer modeling.
  
  
  RESULTS
  Homomeric mutant KCNQ1-S277L channels were unable to carry current, either alone or with KCNE1. When co-expressed in a 50/50 ratio with WT KCNQ1, current density was reduced in a dominant-negative manner, with the residual current predominantly wild type. There was no change in the activation rate and minimal changes to voltage-dependent activation for both KCNQ1 current and I(Ks) current. Immunofluorescence confocal imaging revealed reduced surface expression of mutant KCNQ1-S277L, which was biochemically confirmed by surface biotinylation showing a 44% decrease in mutant surface expression. Expression of KCNQ1-S277L with human ether-a-go-go-related gene (HERG) did not significantly affect HERG protein or current density compared to KCNQ1-WT co-expression.
  
  
  CONCLUSIONS
  The KCNQ1-S277L mutation causes biophysical defects that result in dominant-negative reduction in KCNQ1 and I(Ks) current density, and a trafficking defect that results in reduced surface expression, both without affecting HERG/I(Kr) . KCNQ1-S277L mutation in the proband resulted in defective channels that compromised repolarization reserve, thereby enhancing the arrhythmic susceptibility to pharmacological blockage of I(Kr) current.
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Jerri
authors: J
authors: Chen
authors: Michael
authors: M
authors: Weber
authors: Sung Yon
authors: SY
authors: Um
authors: Christine A
authors: CA
authors: Walsh
authors: Yingying
authors: Y
authors: Tang
authors: Thomas V
authors: TV
authors: McDonald
mesh_terms: D000328:Adult; D003042:Cocaine / Q000009:adverse effects; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000502:physiology*; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D014662:Vasoconstrictor Agents / Q000009:adverse effects
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D014662:Vasoconstrictor Agents; D003042:Cocaine