SCN4A sodium channel, voltage-gated, type IV, alpha subunit [Homo sapiens] - Gene

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Summary

Official Symbol: SCN4Aprovided by HGNC
Official Full Name: sodium channel, voltage-gated, type IV, alpha subunitprovided by HGNC
Primary source: HGNC:10591
See related: Ensembl:ENSG00000007314; HPRD:04912; MIM:603967
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: HYPP; SkM1; HYKPP; NAC1A; HOKPP2; Nav1.4; Na(V)1.4
Summary: Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

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Genomic context

Location :: 17q23.3

Sequence :: Chromosome: 17; NC_000017.10 (62015914..62050278, complement)

See SCN4A in Epigenomics, MapViewer

Chromosome 17 - NC_000017.10 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

A minority of sporadic periodic paralysis patients studied have de novo CACNA1S or SCN4A mutations and may have a variant of familial periodic paralysis.
Title: Genotype and phenotype analysis of patients with sporadic periodic paralysis.
Substitutions at position 799 of the Nav1.4 channel favor the channel open state with sustained activity leading to hyperexcitability of laryngeal muscles that could be lethal during infancy.
Title: Mechanisms underlying a life-threatening skeletal muscle Na+ channel disorder.
L1436P mutation in the SCN4A gene causes a sodium channel myotonia with an atypical clinical presentation, characterized by late onset painful cold-aggravated myotonia
Title: Late onset painful cold-aggravated myotonia: three families with SCN4A L1436P mutation.
This study demonistrated that mutation of Met1592Val in the SCN4A gene is associated with aggressive development of paralysis periodica paramyotonia characterized by severe vacuolar myopathy.
Title: Severe phenotypes of paralysis periodica paramyotonia are associated with the Met1592Val mutation in the voltage-gated sodium channel gene (SCN4A) in a Chinese family.
The skeletal muscle alpha-subunit NaV1.4 was transiently expressed in wild-type Chinese hamster ovary (CHO) cells
Title: Defective polysialylation and sialylation induce opposite effects on gating of the skeletal Na+ channel NaV1.4 in Chinese hamster ovary cells.
ranolazine interacts with the open state and stabilizes the inactivated state(s) of Na(v)1.4 channels, causes voltage- and use-dependent block of I(Na) and suppresses persistent I(Na)
Title: Ranolazine block of human Na v 1.4 sodium channels and paramyotonia congenita mutants.
Anthopleurin elicited opposing effects on the gating mode, kinetics and charge immobilized during open- versus closed-state fast inactivation of Nav1.4 channels.
Title: Open- and closed-state fast inactivation in sodium channels: differential effects of a site-3 anemone toxin.
study detected the SCN4A R672H mutation in one hypokalemic periodic paralysis Turkish family
Title: Hypokalemic periodic paralysis due to the SCN4A R672H mutation in a Turkish family.
Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers.
Title: Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder.
electrostatic network interactions between S2 and other transmembrane segments within Na(v)1.4D4 are similar to but not identical to those proposed for K+ channels
Title: Studies of alpha-helicity and intersegmental interactions in voltage-gated Na+ channels: S2D4.

Submit: New GeneRIF Correction See all (47)

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Phenotypes

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Hyperkalemic periodic paralysis, type 2

MIM: 170500

Hypokalemic periodic paralysis

MIM: 170400

Hypokalemic periodic paralysis (HOKPP) is characterized by a paralytic form and a myopathic form. The paralytic form is characterized by attacks of reversible flaccid paralysis with concomitant hypokalemia, usually leading to paraparesis or tetraparesis but sparing the respiratory muscles and heart. Acute paralytic crises usually last at least several hours and sometimes days. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are carbohydrate-rich meals and rest after exercise; rarely, cold-induced hypokalemic paralysis has been reported. The interval between crises may vary and may be prolonged by preventive treatment with potassium salts or acetazolamide. The age of onset of the first attack ranges from one to 20 years; the frequency of attacks is highest between ages 15 and 35 and then decreases with age. The myopathic form develops in approximately 25% of affected individuals and results in a progressive fixed muscle weakness that begins at variable ages as exercise intolerance predominantly in the lower limbs. It occurs independent of paralytic symptoms and may be the sole manifestation of HOKPP. Individuals with HOKPP are at increased risk for pre- or post-anesthetic weakness and have a risk for malignant hyperthermia that is increased but not as high as that for individuals with true autosomal dominant malignant hyperthermia susceptibility (MHS).

Diagnosis Testing

The diagnosis of HOKPP is based on a history of episodes of flaccid paralysis; low serum concentration of potassium (<0.9 to 3.0 mmol/L) during attacks, but not between attacks; the absence of myotonia clinically and on electromyography (EMG) (with the exception of one family with heat-induced myotonia and cold-induced HOKPP); the absence of hyperthyroidism; the absence of dysmorphic traits and cardiac arrhythmias; and a family history consistent with autosomal dominant inheritance. Of all individuals meeting diagnostic criteria for HOKPP, approximately 55%-70% have mutations in CACNA1S and approximately 8%-10% in SCN4A. Molecular genetic testing is clinically available.

Genetic Counseling

HOKPP is inherited in an autosomal dominant manner. Most individuals diagnosed with HOKPP have an affected parent. The proportion of cases caused by a de novo gene mutation is unknown. Offspring of a proband have a 50% risk of inheriting the mutation. Penetrance is about 90% in males and may be as low as 50% in females depending on the causative mutation. Prenatal testing is possible if the disease-causing mutation has been identified in the family; however, requests for prenatal testing for conditions such as HOKPP that do not affect intellect and have some treatment available are not common.

Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
NP_000325.3	NP_008819.1	CALM1	BIND	PubMed	Nav1.4 interacts with CaM. This interaction was modeled on a demonstrated interaction between rat Nav1.4 and human CaM.
P35499	Q12959	DLG1	HPRD	PubMed
P35499	Q15700	DLG2	HPRD	PubMed
P35499	Q92796	DLG3	HPRD	PubMed
P35499	Q8NI35	INADL	HPRD	PubMed
P35499	Q13424	SNTA1	HPRD	PubMed
P35499	Q13884	SNTB1	HPRD	PubMed
P35499	Q13425	SNTB2	HPRD	PubMed
BioGRID:112234	BioGRID:114769	SLC9A3R1	BioGRID	PubMed	Protein-peptide

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General gene information

Markers

Scn3a (e-PCR), detects polymorphism
- UniSTS:516640

Scn4a (e-PCR), detects polymorphism
- UniSTS:516642

RH66541 (e-PCR)
- UniSTS:46381

RH77871 (e-PCR)
- UniSTS:83006

D2S2975 (e-PCR)
- UniSTS:74585

STS-M81758 (e-PCR)
- UniSTS:10376

GDB:186996 (e-PCR)
- UniSTS:155528

GDB:186997 (e-PCR)
- UniSTS:155529

Genotypes

See SCN4A SNP Geneview Report
See SCN4A SNP Genotype Report
See SCN4A SNP Variation Viewer Report

Homology

Homologs of the SCN4A gene: The SCN4A gene is conserved in chimpanzee, , dog, cow, mouse, rat, zebrafish, fruit fly, and mosquito.
Map Viewer (Mouse, Rat)

Pathways from BioSystems

Axon guidance, organism-specific biosystem (from REACTOME)
Axon guidance, organism-specific biosystemAxon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, w...
Developmental Biology, organism-specific biosystem (from REACTOME)
Developmental Biology, organism-specific biosystemAs a first step towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of three kinds of processes have been annotated. These are a...
Interaction between L1 and Ankyrins, organism-specific biosystem (from REACTOME)
Interaction between L1 and Ankyrins, organism-specific biosystemAnkyrins are a family of adaptor proteins that couple membrane proteins such as voltage gated Na+ channels and the Na+/K+ anion exchanger to the spectrin actin cytoskeleton. Ankyrins are encoded by t...
L1CAM interactions, organism-specific biosystem (from REACTOME)
L1CAM interactions, organism-specific biosystemThe L1 family of cell adhesion molecules (L1CAMs) are a subfamily of the immunoglobulin superfamily of transmembrane receptors, comprised of four structurally related proteins: L1, Close Homolog of L...

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
voltage-gated ion channel activity	IEA Inferred from Electronic Annotation more info
voltage-gated sodium channel activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
ion transport	IEA Inferred from Electronic Annotation more info
muscle contraction	TAS Traceable Author Statement more info	PubMed
sodium ion transport	TAS Traceable Author Statement more info	PubMed
transmembrane transport	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
integral to plasma membrane	TAS Traceable Author Statement more info	PubMed
membrane	IEA Inferred from Electronic Annotation more info
voltage-gated sodium channel complex	IEA Inferred from Electronic Annotation more info

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General protein information

Preferred Names: sodium channel protein type 4 subunit alpha

Names: sodium channel protein type 4 subunit alpha; sodium channel protein type IV subunit alpha; voltage-gated sodium channel subunit alpha Nav1.4; sodium channel protein skeletal muscle subunit alpha; skeletal muscle voltage-dependent sodium channel type IV alpha subunit

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_011699.1 RefSeqGene

Range

5001..39365

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_000334.4 → NP_000325.4 sodium channel protein type 4 subunit alpha

Status: REVIEWED

Source sequence(s)

AC127029, AY212253, M81758

Consensus CDS

CCDS45761.1

UniProtKB/Swiss-Prot

P35499

Related

ENSP00000396320, ENST00000435607

Conserved Domains (2) summary

pfam00520
Location:1067 – 1294
Blast Score: 368

Ion_trans; Ion transport protein

pfam06512
Location:816 – 1041
Blast Score: 538

Na_trans_assoc; Sodium ion transport-associated

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000017.10 Reference GRCh37.p5 Primary Assembly

Range

62015914..62050278, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000149.1 Alternate HuRef

Range

57383629..57417946, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AC127029.12 (47681..82045)	None
genomic	AF038871.1	AAG43105.1
genomic	CH471109.2	EAW94225.1
		EAW94226.1
genomic	L01983.1	AAA75557.1
genomic	L04216.1	AAB59624.1
genomic	L04217.1	AAB59624.1
genomic	L04218.1	AAB59624.1
genomic	L04219.1	AAB59624.1
genomic	L04220.1	AAB59624.1
genomic	L04221.1	AAB59624.1
genomic	L04222.1	AAB59624.1
genomic	L04223.1	AAB59624.1
genomic	L04224.1	AAB59624.1
genomic	L04225.1	AAB59624.1
genomic	L04226.1	AAB59624.1
genomic	L04227.1	AAB59624.1
genomic	L04228.1	AAB59624.1
genomic	L04229.1	AAB59624.1
genomic	L04230.1	AAB59624.1
genomic	L04231.1	AAB59624.1
genomic	L04232.1	AAB59624.1
genomic	L04233.1	AAB59624.1
genomic	L04234.1	AAB59624.1
genomic	L04235.1	AAB59624.1
genomic	L04236.1	AAB59624.1
genomic	S82622.1	AAB21450.2
genomic	U24693.1	AAC14673.1
mRNA	AY212253.1	AAO83647.1
mRNA	M81758.1	AAA60554.1
other-genetic	BC172375.1	AAI72375.1

Protein Accession	Links
Protein Accession	GenPept Link	UniProtKB Link
O60217	GenPept	UniProtKB/TrEMBL:O60217
P35499.4	GenPept	UniProtKB/Swiss-Prot:P35499
Q9H3L9	GenPept	UniProtKB/TrEMBL:Q9H3L9