title: Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing.
abstract: Genetic mutations of the cardiac sodium channel (SCN5A) specific only to the phenotype of atrial fibrillation have recently been described. However, data on the biophysical properties of SCN5A variants associated with atrial fibrillation are scarce. In a mother and son with lone atrial fibrillation, we identified a novel SCN5A coding variant, K1493R, which altered a highly conserved residue in the DIII-IV linker and was located six amino acids downstream from the fast inactivation motif of sodium channels. Biophysical studies of K1493R in tsA201 cells demonstrated a significant positive shift in voltage-dependence of inactivation and a large ramp current near resting membrane potential, indicating a gain-of-function. Enhanced cellular excitability was observed in transfected HL-1 atrial cardiomyocytes, including spontaneous action potential depolarizations and a lower threshold for action potential firing. These novel biophysical observations provide molecular evidence linking cellular "hyperexcitability" as a mechanism inducing vulnerability to this common arrhythmia.
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ont., Canada.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Li
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Gele
authors.initials: G
authors.lastname: Liu
authors.forename: Khanh
authors.initials: K
authors.lastname: Lam
authors.forename: Julie
authors.initials: J
authors.lastname: Rutberg
authors.forename: Martin S
authors.initials: MS
authors.lastname: Green
authors.forename: David H
authors.initials: DH
authors.lastname: Birnie
authors.forename: Robert
authors.initials: R
authors.lastname: Lemery
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
mesh_terms: D000200:Action Potentials / Q000235:genetics*; D000595:Amino Acid Sequence; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels