Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

Ann Med. 2006;38(4):294-304. doi: 10.1080/07853890600756065.


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.

Aim: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • COS Cells
  • Child, Preschool
  • Chlorocebus aethiops
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / genetics*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Female
  • Finland
  • Genetic Carrier Screening*
  • Heterozygote
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • KCNQ1 Potassium Channel / metabolism
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology
  • Male
  • Membrane Potentials
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Mutation
  • NAV1.5 Voltage-Gated Sodium Channel
  • Sodium Channels / genetics
  • Sodium Channels / metabolism
  • Transfection


  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels