SCN4A Membrane Protein Introduction

Introduction of SCN4A

The skeletal muscle sodium channel gene SCN4A is located on chromosome 17q23-25. It encodes the pore-forming α-subunit of the voltage-gated sodium channel expressed in skeletal muscle, known as sodium channel protein type 4 subunit alpha. The α-subunit consists of 4 homologous domains (DI-DIV), and each domain possesses six hydrophobic putative transmembrane helices (S1-S6). The majority of causative SCN4A mutations are missense, and gain of function mutations are usually located within the pore-forming segments S5-S6, the voltage sensor segment S4 or the S4-S5 linker of the SCN4A channel.

Basic Information of SCN4A
Protein Name	Sodium channel protein type 4 subunit alpha
Gene Name	SCN4A
Aliases	SkM1, Sodium channel protein skeletal muscle subunit alpha, Sodium channel protein type IV subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.4
Organism	Homo sapiens (Human)
UniProt ID	P35499
Transmembrane Times	24
Length (aa)	1836
Sequence	MARPSLCTLVPLGPECLRPFTRESLAAIEQRAVEEEARLQRNKQMEIEEPERKPRSDLEAGKNLPMIYGDPPPEVIGIPLEDLDPYYSNKKTFIVLNKGKAIFRFSATPALYLLSPFSVVRRGAIKVLIHALFSMFIMITILTNCVFMTMSDPPPWSKNVEYTFTGIYTFESLIKILARGFCVDDFTFLRDPWNWLDFSVIMMAYLTEFVDLGNISALRTFRVLRALKTITVIPGLKTIVGALIQSVKKLSDVMILTVFCLSVFALVGLQLFMGNLRQKCVRWPPPFNDTNTTWYSNDTWYGNDTWYGNEMWYGNDSWYANDTWNSHASWATNDTFDWDAYISDEGNFYFLEGSNDALLCGNSSDAGHCPEGYECIKTGRNPNYGYTSYDTFSWAFLALFRLMTQDYWENLFQLTLRAAGKTYMIFFVVIIFLGSFYLINLILAVVAMAYAEQNEATLAEDKEKEEEFQQMLEKFKKHQEELEKAKAAQALEGGEADGDPAHGKDCNGSLDTSQGEKGAPRQSSSGDSGISDAMEELEEAHQKCPPWWYKCAHKVLIWNCCAPWLKFKNIIHLIVMDPFVDLGITICIVLNTLFMAMEHYPMTEHFDNVLTVGNLVFTGIFTAEMVLKLIAMDPYEYFQQGWNIFDSIIVTLSLVELGLANVQGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQLFGKSYKECVCKIALDCNLPRWHMHDFFHSFLIVFRILCGEWIETMWDCMEVAGQAMCLTVFLMVMVIGNLVVLNLFLALLLSSFSADSLAASDEDGEMNNLQIAIGRIKLGIGFAKAFLLGLLHGKILSPKDIMLSLGEADGAGEAGEAGETAPEDEKKEPPEEDLKKDNHILNHMGLADGPPSSLELDHLNFINNPYLTIQVPIASEESDLEMPTEEETDTFSEPEDSKKPPQPLYDGNSSVCSTADYKPPEEDPEEQAEENPEGEQPEECFTEACVQRWPCLYVDISQGRGKKWWTLRRACFKIVEHNWFETFIVFMILLSSGALAFEDIYIEQRRVIRTILEYADKVFTYIFIMEMLLKWVAYGFKVYFTNAWCWLDFLIVDVSIISLVANWLGYSELGPIKSLRTLRALRPLRALSRFEGMRVVVNALLGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYYCINTTTSERFDISEVNNKSECESLMHTGQVRWLNVKVNYDNVGLGYLSLLQVATFKGWMDIMYAAVDSREKEEQPQYEVNLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGKDIFMTEEQKKYYNAMKKLGSKKPQKPIPRPQNKIQGMVYDLVTKQAFDITIMILICLNMVTMMVETDNQSQLKVDILYNINMIFIIIFTGECVLKMLALRQYYFTVGWNIFDFVVVILSIVGLALSDLIQKYFVSPTLFRVIRLARIGRVLRLIRGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYSIFGMSNFAYVKKESGIDDMFNFETFGNSIICLFEITTSAGWDGLLNPILNSGPPDCDPNLENPGTSVKGDCGNPSIGICFFCSYIIISFLIVVNMYIAIILENFNVATEESSEPLGEDDFEMFYETWEKFDPDATQFIAYSRLSDFVDTLQEPLRIAKPNKIKLITLDLPMVPGDKIHCLDILFALTKEVLGDSGEMDALKQTMEEKFMAANPSKVSYEPITTTLKRKHEEVCAIKIQRAYRRHLLQRSMKQASYMYRHSHDGSGDDAPEKEGLLANTMSKMYGHENGNSSSPSPEEKGEAGDAGPTMGLMPISPSDTAWPPAPPPGQTVRPGVKESLV

Function of SCN4A Membrane Protein

This SCN4A membrane protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, SCN4A forms a sodium-selective channel through which Na⁺ ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle. Mutations that decrease Na⁺ channel function generally lead to periodic paralysis phenotypes, while increased channel activity, or non-inactivated channels, result in non-dystrophic myotonia phenotypes. Mutations in SCN4A are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis, hypokalemic periodic paralysis type 2, paramyotonia congenital, sodium channel myotonias and congenital myasthenic syndrome.

Fig.1 Scheme of skeletal muscle sodium channel Nav1.4 encoded by SCN4A and the identified mutations. (Tsujino, 2003)

Application of SCN4A Membrane Protein in Literature

Wang X.Y., et al. Mutation analysis of CACNA1S and SCN4A in patients with hypokalemic periodic paralysis. Molecular Medicine Reports. 2015, 12(4):6267-74. PubMed ID: 26252573

This article finds that mutations in CACNA1S and SCN4A are relatively rare in Chinese HPP cases compared with cases in Western individuals.
Heidari M.M., et al. Mutation analysis in exons 22 and 24 of SCN4A gene in Iranian patients with non-dystrophic myotonia. Iranian Journal of Neurology. 2015, 14(4):190-4. PubMed ID: 26885337

This article suggests that the single nucleotide polymorphisms in SCN4A gene play a role in Iranian patients with non-dystrophic myotonias.
Liu X.L., et al. Mutations of SCN4A gene cause different diseases: 2 case reports and literature review. Channels (Austin). 2015, 9(2):82-7. PubMed ID: 25839108

This article provides guidance for diagnosis by summarizing clinical features of the 2 mutations and establishes the genotype-phenotype correlations.
Bugiardini E., et al. SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype. Neuromuscular disorders. 2015, 25(4):301-7. PubMed ID: 25660391

This article reveals that SCN4A mutations may be an enhancer of the myotonic dystrophy type 2 phenotype. Further screening of SCN4A in DM2 cases with atypical myotonic phenotype is likely to reveal other cases in the future.
Singh R.R., et al. Mutations in SCN4A: a rare but treatable cause of recurrent life-threatening laryngospasm. Pediatrics. 2014, 134(5): e1447-5. PubMed ID: 25311598

This article suggests that mutations in SCN4A should be considered as differential diagnosis of recurrent life-threatening laryngospasm infantile.

SCN4A Preparation Options

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Reference

Tsujino A, et al. (2003). Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci USA. 100(12): 7377-82.

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