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MOG1 rescues defective trafficking of Na(v)1.5 mutations in Brugada syndrome and sick sinus syndrome.

ABSTRACT: Loss-of-function mutations in Na(v)1.5 cause sodium channelopathies, including Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome; however, no effective therapy exists. MOG1 increases plasma membrane (PM) expression of Na(v)1.5 and sodium current (I(Na)) density, thus we hypothesize that MOG1 can serve as a therapeutic target for sodium channelopathies.Knockdown of MOG1 expression using small interfering RNAs reduced Na(v)1.5 PM expression, decreased I(Na) densities by 2-fold in HEK/Na(v)1.5 cells and nearly abolished I(Na) in mouse cardiomyocytes. MOG1 did not affect Na(v)1.5 PM turnover. MOG1 small interfering RNAs caused retention of Na(v)1.5 in endoplasmic reticulum, disrupted the distribution of Na(v)1.5 into caveolin-3-enriched microdomains, and led to redistribution of Na(v)1.5 to noncaveolin-rich domains. MOG1 fully rescued the reduced PM expression and I(Na) densities by Na(v)1.5 trafficking-defective mutation D1275N associated with sick sinus syndrome/dilated cardiomyopathy/atrial arrhythmias. For Brugada syndrome mutation G1743R, MOG1 restored the impaired PM expression of the mutant protein and restored I(Na) in a heterozygous state (mixture of wild type and mutant Na(v)1.5) to a full level of a homozygous wild-type state.Use of MOG1 to enhance Na(v)1.5 trafficking to PM may be a potential personalized therapeutic approach for some patients with Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome in the future.

SUBMITTER: Chakrabarti S

PROVIDER: S-EPMC3633223 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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MOG1 rescues defective trafficking of Na(v)1.5 mutations in Brugada syndrome and sick sinus syndrome.

Chakrabarti Susmita S Wu Xiaofen X Yang Zhaogang Z Wu Ling L Yong Sandro L SL Zhang Cuntai C Hu Keli K Wang Qing K QK Chen Qiuyun Q

Circulation. Arrhythmia and electrophysiology 20130218 2

<h4>Background</h4>Loss-of-function mutations in Na(v)1.5 cause sodium channelopathies, including Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome; however, no effective therapy exists. MOG1 increases plasma membrane (PM) expression of Na(v)1.5 and sodium current (I(Na)) density, thus we hypothesize that MOG1 can serve as a therapeutic target for sodium channelopathies.<h4>Methods and results</h4>Knockdown of MOG1 expression using small interfering RNAs reduced Na(v)1.5 PM expre ...[more]

PMID: 23420830

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Project description:RationaleFamilial sick sinus syndrome (SSS) has been linked to loss-of-function mutations of the SCN5A gene, which result in decreased inward Na(+) current, I(Na). However, the functional role of I(Na) in cardiac pacemaking is controversial, and mechanistic links between mutations and sinus node dysfunction in SSS are unclear.ObjectiveTo determine mechanisms by which the SCN5A mutations impair cardiac pacemaking.Methods and resultsAction potential (AP) models for rabbit sinoatrial node (SAN) cells were modified to incorporate experimentally reported I(Na) changes induced by 2 groups of SCN5A gene mutations (affecting the activation and inactivation of I(Na), respectively). The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Effects of the mutations and vagal nerve activity on cardiac pacemaking at the single-cell and tissue levels were studied. Multielectrode extracellular potential recordings of activation pattern from intact SAN-atrium preparations were performed to test predictions of the models. At the single-cell level, the mutations slowed down pacemaking rates in peripheral, but not in central SAN cells that control the heart rhythm. However, in tissue simulations, the mutations not only slowed down pacemaking, but also compromised AP conduction across the SAN-atrium, leading to a possible SAN exit block or sinus arrest, the major features of SSS. Simulated vagal nerve activity amplified the bradycardiac effects of the mutations. Two groups of SCN5A mutations showed subtle differences in impairing the ability of the SAN to drive the surrounding atrium, primarily attributable to their differential effects on atrial excitability and conduction safety. Experimental data with tetrodotoxin and carbachol confirmed the simulation outcomes.ConclusionsOur study substantiates the causative link between SCN5A gene mutations and SSS and illustrates mechanisms by which the mutations impair the driving ability of the SAN.

Project description:Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual). Targeted exome sequencing was used to screen exons and adjacent splice sites of 61 inherited arrhythmia?associated genes, to detect pathogenic genes and variant sites in the proband. Family members were sequenced by Sanger sequencing and protein functions predicted by Polyphen?2 software. A total of three rare variants were identified in the family, including two missense variants in calcium voltage?gated channel subunit alpha1 C (CACNA1C) (gi:193788541, NM_001129843), c.1786G>A (p.V596M) and c.5344G>A (p.A1782T), and one missense variant in titin (TTN) c.49415G>A (p.R16472H) (gi:291045222, NM_003319). The variants p.V596M and p.R16472H were predicted to be deleterious and resulted in alterations in the amino acid type and sequence of the polypeptide chain, which may partially or completely inactivate the encoded protein. The comparison of literature, gene database, and pedigree phenotype analysis suggests that p.V596M or p.R16472H variants are pathogenic. The complex overlapping variants at three loci lead to a more severe phenotype in the proband, and may increase the susceptibility of individuals to atrial fibrillation. The simultaneous occurrence of V596M and R16472H may increase the severity of early repolarization. Various family members may have carried heterozygous mutants of p.A1782T and p.R16472H due to genetic heterogeneity, however did not exhibit clinical signs of cardiac electrophysiological alterations, potentially attributable to the low vagal tone. To the best of the author's knowledge, this is the first study to suggest the involvement of the novel missense CACNA1C c.1786G>A and TTN c.49415G>A variants in the inheritance of symptomatic bradycardia and development of SSS.

Dataset Information

MOG1 rescues defective trafficking of Na(v)1.5 mutations in Brugada syndrome and sick sinus syndrome.

Publications

MOG1 rescues defective trafficking of Na(v)1.5 mutations in Brugada syndrome and sick sinus syndrome.

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