title: Sudden death associated with short-QT syndrome linked to mutations in HERG.
abstract: BACKGROUND
  Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.
  
  
  RESULTS
  Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers.
  
  
  CONCLUSIONS
  We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
authors.affiliation: Molecular Genetics Program, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501, USA. brugada@mmrl.edu
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Kui
authors.initials: K
authors.lastname: Hong
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cordeiro
authors.forename: Fiorenzo
authors.initials: F
authors.lastname: Gaita
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Menendez
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.forename: Guido D
authors.initials: GD
authors.lastname: Pollevick
authors.forename: Christian
authors.initials: C
authors.lastname: Wolpert
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Matsuo
authors.forename: Yue Sheng
authors.initials: YS
authors.lastname: Wu
authors.forename: Alejandra
authors.initials: A
authors.lastname: Guerchicoff
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.forename: Carla
authors.initials: C
authors.lastname: Giustetto
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000401:mortality; D002460:Cell Line; D016757:Death, Sudden, Cardiac; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D007473:Ion Channels / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D013577:Syndrome
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated