In silico investigation of a KCNQ1 mutation associated with familial atrial fibrillation

J. C. Hancox*, S. Kharche, A. El Harchi, J. Stott, P. Law, Haifei Zhang

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)


Mutations in transmembrane domains of the KCNQ1 subunit of the I(Ks) potassium channel have been associated with familial atrial fibrillation. We have investigated mechanisms by which the S1 domain S140G KCNQ1 mutation influences atrial arrhythmia risk and, additionally, whether it can affect ventricular electrophysiology. In perforated-patch recordings, S140G-KCNQ1+KCNE1 exhibited leftward-shifted activation, slowed deactivation and marked residual current. In human atrial action potential (AP) simulations, AP duration and refractoriness were shortened and rate-dependence flattened. Simulated I(Ks) but not I(Kr) block offset AP shortening produced by the mutation. In atrial tissue simulations, temporal vulnerability to re-entry was little affected by the S140G mutation. Spatial vulnerability was markedly increased, leading to more stable and stationary spiral wave re-entry in 2D stimulations, which was offset by I(Ks) block, and to scroll waves in 3D simulations. These changes account for vulnerability to AF with this mutation. Ventricular AP clamp experiments indicate a propensity for increased ventricular I(Ks) with the S140G KCNQ1 mutation and ventricular AP simulations showed model-dependent ventricular AP abbreviation.

Original languageEnglish
Pages (from-to)158-165
Number of pages8
JournalJournal of Electrocardiology
Issue number2
Publication statusPublished - 15 Jan 2014

Bibliographical note

Copyright © 2014 Elsevier Inc. All rights reserved.


  • Action Potentials
  • Animals
  • Atrial Fibrillation
  • CHO Cells
  • Computer Simulation
  • Cricetulus
  • Humans
  • KCNQ1 Potassium Channel
  • Mutation
  • Patch-Clamp Techniques
  • Ventricular Dysfunction

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