title: Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients.
abstract: BACKGROUND
  Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death.
  
  
  OBJECTIVE
  The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study.
  
  
  METHODS
  To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells.
  
  
  RESULTS
  The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect.
  
  
  CONCLUSIONS
  The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.
authors.affiliation: Biomedicum Helsinki and Department of Medicine, University of Helsinki, Finland, and Service of Cardiology, University Hospital, Lausanne, Switzerland. heidi.fodstad@helsinki.fi
authors.forename: Heidi
authors.initials: H
authors.lastname: Fodstad
authors.forename: Saïd
authors.initials: S
authors.lastname: Bendahhou
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Laitinen-Forsblom
authors.forename: Jacques
authors.initials: J
authors.lastname: Barhanin
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Laurent
authors.initials: L
authors.lastname: Schild
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005387:Finland; D006580:Genetic Carrier Screening; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels