Abstract
BackgroundMutations 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 resultsWe 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. ConclusionsThis 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.
Highlights
Mutations in SCN5A encoding the main voltage-gated sodium channel α-subunit in the heart (NaV1.5) [1] have been associated with a spectrum of cardiac arrhythmias including congenital long QT syndrome [2], Brugada syndrome [3], sick sinus syndrome [4,5], progressive cardiac conduction defect [6], atrial fibrillation (AF) [7], and more recently, multifocal ectopic Purkinje-related premature contraction (MEPPC) [8,9]
MEPPC, a recently identified novel SCN5A-related channelopathy, is characterized by frequent premature ventricular contractions (PVCs) arising from the Purkinje system that occur at rest and that are suppressed at high heart rates
We present a relatively large Dutch family with supraventricular arrhythmias including AF, and ventricular arrhythmias, including polymorphic non-sustained ventricular tachycardia (NSVT), with a likely important adrenergic component, we cannot exclude that increased heart rate only is the triggering factor
Summary
Mutations in SCN5A encoding the main voltage-gated sodium channel α-subunit in the heart (NaV1.5) [1] have been associated with a spectrum of cardiac arrhythmias including congenital long QT syndrome [2], Brugada syndrome [3], sick sinus syndrome [4,5], progressive cardiac conduction defect [6], atrial fibrillation (AF) [7], and more recently, multifocal ectopic Purkinje-related premature contraction (MEPPC) [8,9]. 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
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