A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.

Journal Article (Journal Article)

BACKGROUND: Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. METHODS AND RESULTS: We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the "late" Na(+) current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current. CONCLUSIONS: The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism.

Full Text

Duke Authors

Cited Authors

  • Wang, H-G; Zhu, W; Kanter, RJ; Silva, JR; Honeywell, C; Gow, RM; Pitt, GS

Published Date

  • March 2016

Published In

Volume / Issue

  • 92 /

Start / End Page

  • 52 - 62

PubMed ID

  • 26801742

Pubmed Central ID

  • PMC4789166

Electronic International Standard Serial Number (EISSN)

  • 1095-8584

Digital Object Identifier (DOI)

  • 10.1016/j.yjmcc.2016.01.014


  • eng

Conference Location

  • England