Microscopic mechanisms for long QT syndrome type 1 revealed by single-channel analysis of I(Ks) with S3 domain mutations in KCNQ1

Heart Rhythm. 2015 Feb;12(2):386-94. doi: 10.1016/j.hrthm.2014.10.029. Epub 2014 Oct 29.


Background: The slowly activating delayed rectifier current IKs participates in cardiac repolarization, particularly at high heart rates, and mutations in this K(+) channel complex underlie long QT syndrome (LQTS) types 1 and 5.

Objective: The purpose of this study was to determine biophysical mechanisms of LQT1 through single-channel kinetic analysis of IKs carrying LQT1 mutations in the S3 transmembrane region of the pore-forming subunit KCNQ1.

Methods: We analyzed cell-attached recordings from mammalian cells in which a single active KCNQ1 (wild type or mutant) and KCNE1 complex could be detected.

Results: The S3 mutants of KCNQ1 studied (D202H, I204F, V205M, and S209F), with the exception of S209F, all led to a reduction in channel activity through distinct kinetic mechanisms. D202H, I204F, and V205M showed decreased open probability (Po) compared with wild type (0.07, 0.04, and 0.12 vs 0.2); increased first latency from 1.66 to >2 seconds at +60 mV (I204F, V205M); variable-to-severe reductions in open dwell times (≥50% in V205M); stabilization of closed states (D202H); and an inability of channels to reach full conductance levels (V205M, I204F). S209F is a kinetic gain-of-function mutation with a high Po (0.40) and long open-state dwell times.

Conclusion: S3 mutations in KCNQ1 cause diverse kinetic defects in I(Ks), affecting opening and closing properties, and can account for LQT1 phenotypes.

Keywords: Cardiac arrhythmia; Electrophysiology; KCNQ1 potassium channel; Long QT syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA / genetics*
  • DNA Mutational Analysis
  • Disease Models, Animal
  • KCNQ1 Potassium Channel / genetics*
  • KCNQ1 Potassium Channel / metabolism
  • Mice, Transgenic
  • Mutation*
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Phenotype
  • Romano-Ward Syndrome / genetics*
  • Romano-Ward Syndrome / metabolism
  • Romano-Ward Syndrome / pathology


  • KCNQ1 Potassium Channel
  • DNA