Cardiac sodium channel mutations: why so many phenotypes?

Abstract

Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies.

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

“…Such “loss-of-function” is the characteristic of Brugada syndrome (BrS) or cardiac conduction disturbance (CCD) [4]. However, there was no ECG evidence of Brugada-type ST elevation, right bundle branch block morphology or conduction disorders seen in this patient.…”

“…Phenotypic variability arises from the effects of the mutations on the hNa v 1.5 biophysical properties. These effects usually fall into two categories, gain or loss of channel function [4]. In “gain-of-function” mutations, an increase in the persistent late I Na during the action potential plateau, rather than in peak I Na is typically thought to be responsible for the type 3 long QT syndrome (LQT3) phenotype whereby repolarization is delayed and the QT interval is prolonged on the surface electrocardiogram (ECG) [5].…”

Mutations of SCN4A gene cause different diseases: 2 case reports and literature review

“…In addition, individual Nav channel mutations can have more than one physiological phenotype can also be found in the predominant heart sodium channel isoform, Nav1.5, which might be the result of additional modifiers of channel behavior, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. 21 Above-mentioned mechanisms in connection with Nav1.5 may be one of contributing interpretations for phenotypic variability in Nav1.4.In addition, the exact pathophysiologic mechanisms how these mutations in SCN4A gene result in 2 different diseases such as paramyotonia congenita and hypokalemic periodic paralysis are not identified.…”

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies

“…Besides the known mutations in several genes (SCN5A, GPD1L, SCN1B, SCN2B, SCN3B, MOG1, RANGRF, SLMAP, KCNE3, KCNJ8, HCN4, KCNE5, KCND3, CACNA1C, CACNB2, CACNA2D1, SCN10A and TRPM4), 2,3 other factors also have an important role in the resulting phenotype such as additional variants 54 (compound heterozygous disease-associated polymorphisms in family A), 15,16,55 epigenetic mechanisms (DNA methylation, posttranslational modifications and RNA mechanisms) 56 and phenotype modulators (vagal tone, sex hormones and febrile status). 57 It is likely that these additional factors influence the precise phenotypic expression and are therefore responsible for phenotypic overlap 41 and variable expressivity or incomplete penetrance 58 as seen in these families. As described for SCN10A, which encodes the sodium channel isoform Nav1.8, 54 the presence of an SCN4A variant or a CLCN1 variant or the expansion of a CTG trinucleotide repeat in DMPK, is probably not solely responsible for an arrhythmic event, but would rather act as an additional modifier.…”