Human Gene SCN4A (ENST00000435607.3) Description and Page Index
  Description: Homo sapiens sodium voltage-gated channel alpha subunit 4 (SCN4A), mRNA. (from RefSeq NM_000334)
RefSeq Summary (NM_000334): 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]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: M81758.1, AY212253.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1966682 [ECO:0000350] ##Evidence-Data-END## ##RefSeq-Attributes-START## MANE Ensembl match :: ENST00000435607.3/ ENSP00000396320.1 RefSeq Select criteria :: based on single protein-coding transcript ##RefSeq-Attributes-END##
Gencode Transcript: ENST00000435607.3
Gencode Gene: ENSG00000007314.12
Transcript (Including UTRs)
   Position: hg38 chr17:63,938,554-63,972,918 Size: 34,365 Total Exon Count: 24 Strand: -
Coding Region
   Position: hg38 chr17:63,940,771-63,972,841 Size: 32,071 Coding Exon Count: 24 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesGeneReviewsMethods
Data last updated: 2019-09-04

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr17:63,938,554-63,972,918)mRNA (may differ from genome)Protein (1836 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaBioGPS
CGAPEnsemblEntrez GeneExonPrimerGeneCardsHGNC
HPRDLynxMGImyGene2neXtProtOMIM
PubMedReactomeStanford SOURCEUniProtKBWikipedia

-  Comments and Description Text from UniProtKB
  ID: SCN4A_HUMAN
DESCRIPTION: RecName: Full=Sodium channel protein type 4 subunit alpha; AltName: Full=SkM1; AltName: Full=Sodium channel protein skeletal muscle subunit alpha; AltName: Full=Sodium channel protein type IV subunit alpha; AltName: Full=Voltage-gated sodium channel subunit alpha Nav1.4;
FUNCTION: This 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, the protein 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.
SUBUNIT: Muscle sodium channels contain an alpha subunit and a smaller beta subunit. Interacts with the PDZ domain of the syntrophin SNTA1, SNTB1 and SNTB2 (By similarity).
SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
DOMAIN: The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1,S2,S3,S5,S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.
DISEASE: Defects in SCN4A are the cause of paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]. PMC is an autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, nonprogressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP.
DISEASE: Defects in SCN4A are a cause of periodic paralysis hypokalemic type 2 (HOKPP2) [MIM:613345]. It is an autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels.
DISEASE: Defects in SCN4A are the cause of periodic paralysis hyperkalemic (HYPP) [MIM:170500]. HYPP is an autosomal dominant channelopathy characterized by episodic flaccid generalized muscle weakness associated with high levels of serum potassium. Concurrence of myotonia is found in HYPP patients.
DISEASE: Defects in SCN4A are the cause of periodic paralysis normokalemic (NKPP) [MIM:170500]. NKPP is a disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness.
DISEASE: Defects in SCN4A are the cause of myotonia SCN4A-related (MYOSCN4A) [MIM:608390]. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. Myotonia causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. MYOSCN4A is a phenotypically highly variable myotonia aggravated by potassium loading, and often by cold. MYOSCN4A includes myotonia permanens and myotonia fluctuans. In myotonia permanens, the myotonia is generalized and there is a hypertrophy of the muscle, particularly in the neck and the shoulder. Attacks of severe muscle stiffness of the thoracic muscles may be life threatening due to impaired ventilation. In myotonia fluctuans, the muscle stiffness may fluctuate from day to day, provoked by exercise.
DISEASE: Defects in SCN4A are the cause of a congenital myasthenic syndrome acetazolamide-responsive (CMSAR) [MIM:614198]. A congenital myasthenic syndrome associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involves lid- elevator, external ocular, facial, limb and truncal muscles and an decremental response of the compound muscle action potential on repetitive stimulation.
SIMILARITY: Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.4/SCN4A subfamily.
SIMILARITY: Contains 1 IQ domain.
WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SCN4A";
WEB RESOURCE: Name=Wikipedia; Note=SCN4A entry; URL="http://en.wikipedia.org/wiki/SCN4A";

-  MalaCards Disease Associations
  MalaCards Gene Search: SCN4A
Diseases sorted by gene-association score: paramyotonia congenita* (1704), myotonia congenita, atypical, acetazolamide-responsive* (1650), hypokalemic periodic paralysis, type 2* (1318), hyperkalemic periodic paralysis, type 2* (1232), myasthenic syndrome, congenital, 16* (1229), hypokalemic periodic paralysis, type 1* (623), congenital myasthenic syndrome* (534), normokalemic periodic paralysis* (531), hyperkalemic periodic paralysis type 1* (500), myotonia* (320), postsynaptic congenital myasthenic syndromes* (157), scn4a-related congenital myasthenic syndrome* (100), myotonia congenita (27), familial periodic paralysis (20), periodic paralyses (18), andersen syndrome (13), congenital myopathy (12), malignant hyperthermia (7), critical illness polyneuropathy (7), myotonic dystrophy 2 (7), malignant hyperthermia susceptibility (7), myotonic disease (6), metal metabolism disorder (6), cenani-lenz syndactyly syndrome (5), inflammatory and toxic neuropathy (5), graves disease 1 (5), neuromuscular disease (5), myopathy (4), pseudohyperkalemia, familial, 2, due to red cell leak (4), brugada syndrome (2)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 37.67 RPKM in Muscle - Skeletal
Total median expression: 82.33 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -27.3077-0.355 Picture PostScript Text
3' UTR -881.202217-0.397 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR005821 - Ion_trans_dom
IPR000048 - IQ_motif_EF-hand-BS
IPR008052 - Na_channel_a4su
IPR001696 - Na_channel_asu
IPR010526 - Na_trans_assoc

Pfam Domains:
PF00520 - Ion transport protein
PF06512 - Sodium ion transport-associated

ModBase Predicted Comparative 3D Structure on P35499
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
MGIRGDEnsembl   
Protein SequenceProtein Sequence    
AlignmentAlignment    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0005216 ion channel activity
GO:0005244 voltage-gated ion channel activity
GO:0005248 voltage-gated sodium channel activity
GO:0005272 sodium channel activity

Biological Process:
GO:0006811 ion transport
GO:0006814 sodium ion transport
GO:0006936 muscle contraction
GO:0019228 neuronal action potential
GO:0034220 ion transmembrane transport
GO:0034765 regulation of ion transmembrane transport
GO:0035725 sodium ion transmembrane transport
GO:0055085 transmembrane transport
GO:0086010 membrane depolarization during action potential

Cellular Component:
GO:0001518 voltage-gated sodium channel complex
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0016020 membrane
GO:0016021 integral component of membrane


-  Descriptions from all associated GenBank mRNAs
  M81758 - Homo sapiens skeletal muscle voltage-dependent sodium channel alpha subunit (SkM1) mRNA, complete cds.
AY212253 - Homo sapiens skeletal muscle voltage-dependent sodium channel type IV alpha subunit (SCN4A) mRNA, complete cds.
BC172375 - Synthetic construct Homo sapiens clone IMAGE:100069069, MGC:199080 sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) mRNA, encodes complete protein.
JD118837 - Sequence 99861 from Patent EP1572962.
JD374004 - Sequence 355028 from Patent EP1572962.
JD519706 - Sequence 500730 from Patent EP1572962.
JD219629 - Sequence 200653 from Patent EP1572962.
JD409151 - Sequence 390175 from Patent EP1572962.
JD219628 - Sequence 200652 from Patent EP1572962.
JD233940 - Sequence 214964 from Patent EP1572962.
JD256339 - Sequence 237363 from Patent EP1572962.
JD270819 - Sequence 251843 from Patent EP1572962.
JD293615 - Sequence 274639 from Patent EP1572962.
JD092237 - Sequence 73261 from Patent EP1572962.
JD356181 - Sequence 337205 from Patent EP1572962.
JD075997 - Sequence 57021 from Patent EP1572962.
JD472030 - Sequence 453054 from Patent EP1572962.
JD044477 - Sequence 25501 from Patent EP1572962.
JD271672 - Sequence 252696 from Patent EP1572962.
JD392924 - Sequence 373948 from Patent EP1572962.
JD366880 - Sequence 347904 from Patent EP1572962.
JD536931 - Sequence 517955 from Patent EP1572962.
JD385043 - Sequence 366067 from Patent EP1572962.
JD099820 - Sequence 80844 from Patent EP1572962.
JD166608 - Sequence 147632 from Patent EP1572962.
JD557075 - Sequence 538099 from Patent EP1572962.
JD147502 - Sequence 128526 from Patent EP1572962.
JD419660 - Sequence 400684 from Patent EP1572962.
JD141045 - Sequence 122069 from Patent EP1572962.
JD483565 - Sequence 464589 from Patent EP1572962.
JD323440 - Sequence 304464 from Patent EP1572962.
JD100139 - Sequence 81163 from Patent EP1572962.
JD246594 - Sequence 227618 from Patent EP1572962.
JD154456 - Sequence 135480 from Patent EP1572962.
JD413264 - Sequence 394288 from Patent EP1572962.
JD524491 - Sequence 505515 from Patent EP1572962.
JD390199 - Sequence 371223 from Patent EP1572962.
JD332535 - Sequence 313559 from Patent EP1572962.
JD108784 - Sequence 89808 from Patent EP1572962.
JD523138 - Sequence 504162 from Patent EP1572962.
JD151789 - Sequence 132813 from Patent EP1572962.
JD062362 - Sequence 43386 from Patent EP1572962.
JD042681 - Sequence 23705 from Patent EP1572962.
JD329567 - Sequence 310591 from Patent EP1572962.
JD159791 - Sequence 140815 from Patent EP1572962.
JD159895 - Sequence 140919 from Patent EP1572962.
JD182836 - Sequence 163860 from Patent EP1572962.
JD278524 - Sequence 259548 from Patent EP1572962.
JD538850 - Sequence 519874 from Patent EP1572962.
JD322508 - Sequence 303532 from Patent EP1572962.
JD367755 - Sequence 348779 from Patent EP1572962.
JD103054 - Sequence 84078 from Patent EP1572962.
JD492381 - Sequence 473405 from Patent EP1572962.
JD278111 - Sequence 259135 from Patent EP1572962.
JD527036 - Sequence 508060 from Patent EP1572962.
JD465364 - Sequence 446388 from Patent EP1572962.
JD559294 - Sequence 540318 from Patent EP1572962.
JD273063 - Sequence 254087 from Patent EP1572962.
JD109024 - Sequence 90048 from Patent EP1572962.
JD426270 - Sequence 407294 from Patent EP1572962.
JD155290 - Sequence 136314 from Patent EP1572962.
JD564164 - Sequence 545188 from Patent EP1572962.
JD390226 - Sequence 371250 from Patent EP1572962.
JD180733 - Sequence 161757 from Patent EP1572962.
JD454736 - Sequence 435760 from Patent EP1572962.
JD044529 - Sequence 25553 from Patent EP1572962.
JD460809 - Sequence 441833 from Patent EP1572962.
JD260322 - Sequence 241346 from Patent EP1572962.
JD537835 - Sequence 518859 from Patent EP1572962.
JD054797 - Sequence 35821 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  Reactome (by CSHL, EBI, and GO)

Protein P35499 (Reactome details) participates in the following event(s):

R-HSA-373739 Ankyrins link voltage-gated sodium and potassium channels to spectrin and L1
R-HSA-5576895 SCNAs:SNCBs transport Na+ from extracellular region to cytosol
R-HSA-445095 Interaction between L1 and Ankyrins
R-HSA-5576892 Phase 0 - rapid depolarisation
R-HSA-373760 L1CAM interactions
R-HSA-5576891 Cardiac conduction
R-HSA-422475 Axon guidance
R-HSA-397014 Muscle contraction
R-HSA-1266738 Developmental Biology

-  Other Names for This Gene
  Alternate Gene Symbols: NM_000334, P35499, Q15478, Q16447, Q7Z6B1, SCN4A_HUMAN, uc002jds.1
UCSC ID: uc002jds.1
RefSeq Accession: NM_000334
Protein: P35499 (aka SCN4A_HUMAN or CIN4_HUMAN)
CCDS: CCDS45761.1

-  GeneReviews for This Gene
  GeneReviews article(s) related to gene SCN4A:
hyper-pp (Hyperkalemic Periodic Paralysis)
cms (Congenital Myasthenic Syndromes)
hpp (Hypokalemic Periodic Paralysis)

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.