title: Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures.
abstract: BACKGROUND
  Long QT syndrome (LQTS) is characterized by corrected QT interval prolongation leading to torsades de pointes and sudden cardiac death. LQTS type 2 (LQTS2) is caused by mutations in the KCNH2 gene, leading to a reduction of the rapidly activating delayed rectifier K+ current and loss of human ether-à-go-go-related gene (hERG) channel function by different mechanisms. Triggers for life-threatening arrhythmias in LQTS2 are often auditory stimuli.
  
  
  OBJECTIVE
  To screen KCNH2 for mutations in patients with LQTS2 on an electrocardiogram and auditory-induced syncope interpreted as seizures and sudden cardiac death, and to analyze their impact on the channel function in vitro.
  
  
  METHODS
  The KCNH2 gene was screened for mutations in the index patients of three families. The novel mutations were reproduced in vitro using site-directed mutagenesis and characterized using the Xenopus oocyte expression system in voltage clamp mode.
  
  
  RESULTS
  Novel KCNH2 mutations (Y493F, A429P and del234-241) were identified in the index patients with mostly typical LQTS2 features on their electrocardiograms. The biochemical data revealed a trafficking defect. The biophysical data revealed a loss of function when mutated hERG channels were coexpressed with the wild type.
  
  
  CONCLUSIONS
  In all families, at least one patient carrying the mutation had a history of seizures after auditory stimuli, which is a major trigger for arrhythmic events in LQTS2. Seizures are likely due to cardiac syncope as a consequence of mutation-induced loss of function of the rapidly activating delayed rectifier K+ current.
authors: Cardiology Department, Univesiry Hospital of Basel, Basel, Switzerland.
authors: Dagmar I
authors: DI
authors: Keller
authors: Julie
authors: J
authors: Grenier
authors: Georges
authors: G
authors: Christé
authors: Frédérique
authors: F
authors: Dubouloz
authors: Stefan
authors: S
authors: Osswald
authors: Marijke
authors: M
authors: Brink
authors: Eckhard
authors: E
authors: Ficker
authors: Mohamed
authors: M
authors: Chahine
mesh_terms: D000328:Adult; D000368:Aged; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012640:Seizures / Q000209:etiology*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human