title: In silico investigation of a KCNQ1 mutation associated with familial atrial fibrillation.
abstract: 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.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom; Computational Biology, Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom. Electronic address: jules.hancox@bristol.ac.uk.
authors.forename: J C
authors.initials: JC
authors.lastname: Hancox
authors.affiliation: Computational Biology, Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom; College of Engineering, Mathematics, and Physical Sciences, University of Exeter, Exeter, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Kharche
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: El Harchi
authors.affiliation: Computational Biology, Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Stott
authors.affiliation: Computational Biology, Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Law
authors.affiliation: Computational Biology, Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology*; D016466:CHO Cells; D003198:Computer Simulation; D003412:Cricetulus; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D009154:Mutation; D018408:Patch-Clamp Techniques; D018754:Ventricular Dysfunction / Q000235:genetics / Q000503:physiopathology
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: AF; Atrial fibrillation; I(Ks); Inherited arrhythmia; KCNQ1; Modelling; Re-entry; Simulation; Spiral wave