Genotype–phenotype association in patients with SCN4A mutation

Abstract

Roope Männikkö and colleagues1Männikkö R Wong L Tester DJ et al.Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.Lancet. 2018; 391: 1483-1492Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar described an association between dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, and sudden infant death syndrome (SIDS). The authors found that rare SCN4A variants occurred in infants who died from SIDS. Patch clamp studies presented an alteration of sodium channel kinetics. Our data on patients with muscle disease and risk of sudden cardiac death have shown altered sodium channel kinetics.2El-Battrawy I Zhao Z Lan H et al.Ion channel dysfunctions in dilated cardiomyopathy in limb-girdle muscular dystrophy.Circ Genom Precis Med. 2018; 11e001893 Crossref PubMed Scopus (27) Google Scholar Different sodium channel genes including the SCN5A could affect the sodium channel kinetics and have been associated with sudden cardiac death and SIDS as well.3Bezzina CR Barc J Mizusawa Y et al.Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death.Nat Genet. 2013; 45: 1044-1049Crossref PubMed Scopus (374) Google Scholar Certainly, acknowledging the limitation that Männikkö and colleagues did not report any information about the extracellular solution used for the study of functionality is important. Because the sodium channel family has nine gene members highly presented by the SCN5A gene, the possibility that a relevant part of altered sodium current presented is related to the SCN5A is not excluded. Distinguishing the role of different sodium channel gene family members using patch clamp is dependent on using selective blockers such as tetrodotoxin. Another important point is that the study group did not check for mutations in the SCN10A using whole genome sequencing. Data have confirmed that SCN10A, a sodium channel, is related to sudden cardiac death and that its alteration could affect the peak sodium current and other sodium channel kinetics.4Hu D Barajas-Martinez H Pfeiffer R et al.Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.J Am Coll Cardiol. 2014; 64: 66-79Crossref PubMed Scopus (174) Google Scholar, 5Behr ER Savio-Galimberti E Barc J et al.Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.Cardiovasc Res. 2015; 106: 520-529Crossref PubMed Scopus (81) Google Scholar Finally, we wonder whether the study group saw any alteration of action potential characteristics. Reduced peak sodium current is associated with a reduction in the maximum rate of rise of the action potential, which might be associated with an interval variability of action potentials as an expression of arrhythmia and sudden cardiac death. Therefore, more evidence about other cardiac sodium channel members and action potential characteristics is required before the final conclusion can be made about the association between SCN4A mutations and SIDS. We declare no competing interests. Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control studyRare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. Full-Text PDF Open AccessGenotype–phenotype association in patients with SCN4A mutation – Authors' replyWe are pleased with Ibrahim El-Battrawy and colleagues' interest in our work.1 We note that the authors are concerned that the sodium current recordings in our patch clamp experiments could have been contributed to by NaV1.5. As described in the methods section,1 we assessed expression in HEK293 cells, which do not express endogenous sodium channels. These cells were transfected with mutant and wild-type SCN4A DNA. This approach excludes any possibility of NaV1.5, or any other sodium channel isoform, contributing to the sodium current recordings. Full-Text PDF