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Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation.

Abstract：

BACKGROUND:Mutations in SCN5A, the gene encoding the α-subunit of the cardiac sodium channel (NaV1.5), are associated with a broad spectrum of inherited cardiac arrhythmia disorders. The purpose of this study was to identify the genetic and functional determinants underlying a Dutch family that presented with a combined phenotype of ventricular arrhythmias with a likely adrenergic component, either in isolation or in combination with a mildly decreased heart function and early onset (<55years) atrial fibrillation. METHODS AND RESULTS:We performed next generation sequencing in the proband of a two-generation Dutch family and demonstrated a novel missense mutation in SCN5A-(p.M1851V) which co-segregated with the clinical phenotype in the family. We functionally evaluated the putative genetic defect by patch clamp electrophysiological studies in human embryonic kidney cells transfected with mutant or wild-type Nav1.5. The current inactivation was slower and recovery from inactivation was faster in SCN5A-M1851V channels. The voltage dependence of inactivation was shifted towards more positive potentials and consequently, a larger TTX-sensitive window current was observed in SCN5A-M1851V channels. Furthermore, a higher upstroke velocity was observed for the SCN5A-M1851V channels, while the depolarization voltage was more negative, both indicating increased excitability. CONCLUSIONS:This mutation leads to a gain-of-function mechanism based on increased channel availability and increased window current, fitting the observed clinical phenotype of (likely adrenergic-induced) ventricular arrhythmias and atrial fibrillation. These findings further expand the range of cardiac arrhythmias associated with mutations in SCN5A.

journal_name

Int J Cardiol

journal_title

International journal of cardiology

authors

Lieve KV,Verkerk AO,Podliesna S,van der Werf C,Tanck MW,Hofman N,van Bergen PF,Beekman L,Bezzina CR,Wilde AAM,Lodder EM

doi

10.1016/j.ijcard.2017.01.113

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

187-193

eissn

0167-5273

issn

1874-1754

pii

S0167-5273(16)33462-3

journal_volume

236

pub_type

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Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation.