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

Journal of Molecular and Cellular Cardiology
Hong-Gang WangGeoffrey S Pitt

Abstract

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. 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. The p.R1309H homozygous NaV1.5 mutation conf...Continue Reading

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Citations

Jan 20, 2017·Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation·C J M van OpbergenT A B van Veen
Apr 22, 2017·British Journal of Pharmacology·Wen YuZhiren Zhang
Jul 20, 2017·The Journal of General Physiology·Wandi ZhuJonathan R Silva
Sep 1, 2017·Journal of Neonatal-perinatal Medicine·William N EvansHumberto Restrepo
May 29, 2018·Experimental Biology and Medicine·Dan HanGuoliang Li
Jul 3, 2021·International Journal of Molecular Sciences·Cristina BallaPaola Imbrici
Aug 5, 2021·The Journal of General Physiology·Paweorn AngsutararuxJonathan R Silva
Dec 7, 2021·Frontiers in Pharmacology·Paweorn AngsutararuxJonathan R Silva

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