P35499 (SCN4A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Sodium channel protein type 4 subunit alpha

Alternative name(s):
SkM1
Sodium channel protein skeletal muscle subunit alpha
Sodium channel protein type IV subunit alpha
Voltage-gated sodium channel subunit alpha Nav1.4

Gene names

Name:

SCN4A

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1836 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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 structure	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.
Involvement in disease	Paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]: 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, non-progressive 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.16 Ref.18 Ref.21 Ref.27 Ref.28 Ref.35 Ref.36 Ref.38 Ref.41 Periodic paralysis hypokalemic 2 (HOKPP2) [MIM:613345]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Ref.22 Ref.23 Ref.24 Ref.25 Ref.30 Ref.40 Ref.42 Ref.43 Periodic paralysis hyperkalemic (HYPP) [MIM:170500]: 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Ref.8 Ref.15 Ref.38 Periodic paralysis normokalemic (NKPP) [MIM:170500]: A disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.26 Ref.34 Ref.42 Myotonia SCN4A-related (MYOSCN4A) [MIM:608390]: A phenotypically highly variable myotonia aggravated by potassium loading, and sometimes by cold. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. It 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. Myotonia SCN4A-related 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14 Ref.17 Ref.19 Ref.28 Ref.29 Ref.31 Ref.32 Ref.33 Ref.37 Ref.38 Ref.39 Myasthenic syndrome, congenital, 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3
Sequence similarities	Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.4/SCN4A subfamily. [View classification] Contains 1 IQ domain.

Ontologies

Keywords
Biological process	Ion transport Sodium transport Transport
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Congenital myasthenic syndrome Disease mutation
Domain	Repeat Transmembrane Transmembrane helix
Ligand	Sodium
Molecular function	Ion channel Sodium channel Voltage-gated channel
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	muscle contraction Traceable author statement Ref.9. Source: ProtInc
Cellular_component	integral to plasma membrane Traceable author statement Ref.7. Source: ProtInc voltage-gated sodium channel complex Inferred from electronic annotation. Source: InterPro
Molecular_function	voltage-gated sodium channel activity Traceable author statement Ref.19. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1836	1836	Sodium channel protein type 4 subunit alpha		PRO_0000048495
Regions
	Transmembrane	129 – 150	22	Helical; Name=S1 of repeat I; Potential
	Transmembrane	159 – 178	20	Helical; Name=S2 of repeat I; Potential
	Transmembrane	191 – 210	20	Helical; Name=S3 of repeat I; Potential
	Transmembrane	217 – 236	20	Helical; Voltage-sensor; Name=S4 of repeat I; Potential
	Transmembrane	253 – 266	14	Helical; Name=S5 of repeat I; Potential
	Transmembrane	424 – 449	26	Helical; Name=S6 of repeat I; Potential
	Transmembrane	574 – 597	24	Helical; Name=S1 of repeat II; Potential
	Transmembrane	609 – 632	24	Helical; Name=S2 of repeat II; Potential
	Transmembrane	641 – 660	20	Helical; Name=S3 of repeat II; Potential
	Transmembrane	667 – 686	20	Helical; Voltage-sensor; Name=S4 of repeat II; Potential
	Transmembrane	702 – 724	23	Helical; Name=S5 of repeat II; Potential
	Transmembrane	777 – 802	26	Helical; Name=S6 of repeat II; Potential
	Transmembrane	1027 – 1049	23	Helical; Name=S1 of repeat III; Potential
	Transmembrane	1064 – 1089	26	Helical; Name=S2 of repeat III; Potential
	Transmembrane	1096 – 1116	21	Helical; Name=S3 of repeat III; Potential
	Transmembrane	1122 – 1143	22	Helical; Voltage-sensor; Name=S4 of repeat III; Potential
	Transmembrane	1163 – 1184	22	Helical; Name=S5 of repeat III; Potential
	Transmembrane	1269 – 1295	27	Helical; Name=S6 of repeat III; Potential
	Transmembrane	1349 – 1372	24	Helical; Name=S1 of repeat IV; Potential
	Transmembrane	1384 – 1407	24	Helical; Name=S2 of repeat IV; Potential
	Transmembrane	1414 – 1437	24	Helical; Name=S3 of repeat IV; Potential
	Transmembrane	1447 – 1469	23	Helical; Voltage-sensor; Name=S4 of repeat IV; Potential
	Transmembrane	1485 – 1507	23	Helical; Name=S5 of repeat IV; Potential
	Transmembrane	1574 – 1598	25	Helical; Name=S6 of repeat IV; Potential
	Repeat	128 – 450	323	I
	Repeat	571 – 796	226	II
	Repeat	1024 – 1281	258	III
	Repeat	1349 – 1595	247	IV
	Domain	1727 – 1756	30	IQ
Amino acid modifications
	Glycosylation	214	1	N-linked (GlcNAc...) Potential
	Glycosylation	288	1	N-linked (GlcNAc...) Potential
	Glycosylation	291	1	N-linked (GlcNAc...) Potential
	Glycosylation	297	1	N-linked (GlcNAc...) Potential
	Glycosylation	303	1	N-linked (GlcNAc...) Potential
	Glycosylation	315	1	N-linked (GlcNAc...) Potential
	Glycosylation	321	1	N-linked (GlcNAc...) Potential
	Glycosylation	333	1	N-linked (GlcNAc...) Potential
	Glycosylation	362	1	N-linked (GlcNAc...) Potential
	Glycosylation	507	1	N-linked (GlcNAc...) Potential
	Glycosylation	961	1	N-linked (GlcNAc...) Potential
	Glycosylation	1191	1	N-linked (GlcNAc...) Potential
	Glycosylation	1205	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	135	1	M → V.		VAR_001560
	Natural variant	141	1	I → V in MYOSCN4A; causes a hyperpolarizing shift of the activation curve; enhances channel slow inactivation. Ref.37		VAR_054934
	Natural variant	222	1	R → W in HOKPP2. Ref.40		VAR_054935
	Natural variant	225	1	R → W in MYOSCN4A. Ref.38		VAR_065230
	Natural variant	246	1	S → L. Ref.3		VAR_017785
	Natural variant	270	1	Q → K in PMC. Ref.28 Ref.36		VAR_054936
	Natural variant	445	1	V → M in MYOSCN4A. Ref.17 Ref.19 Ref.39		VAR_017786
	Natural variant	452	1	E → K in MYOSCN4A; variable phenotype ranging from mild to severe myotonia. Ref.39		VAR_054937
	Natural variant	524	1	S → G. Ref.1 Ref.3 Ref.4 Corresponds to variant rs6504191 [ dbSNP | Ensembl ].		VAR_001561
	Natural variant	559	1	N → D. Ref.1 Ref.3 Corresponds to variant rs1047705 [ dbSNP | Ensembl ].		VAR_017787
	Natural variant	669	1	R → H in HOKPP2. Ref.20 Ref.30		VAR_017788
	Natural variant	671	1	F → S in MYOSCN4A. Ref.39		VAR_054938
	Natural variant	672	1	R → C in HOKPP2. Ref.30 Ref.40		VAR_054939
	Natural variant	672	1	R → G in HOKPP2. Ref.23 Ref.30 Ref.40		VAR_017789
	Natural variant	672	1	R → H in HOKPP2. Ref.23 Ref.40 Ref.43		VAR_017790
	Natural variant	672	1	R → S in HOKPP2. Ref.24 Ref.25 Ref.40		VAR_017791
	Natural variant	675	1	R → G in NKPP. Ref.26		VAR_037104
	Natural variant	675	1	R → Q in NKPP. Ref.26 Ref.34		VAR_037105
	Natural variant	675	1	R → W in NKPP. Ref.26		VAR_037106
	Natural variant	693	1	I → T in PMC. Ref.38		VAR_065231
	Natural variant	704	1	T → M in HYPP and PMC. Ref.7 Ref.36 Ref.41		VAR_001562
	Natural variant	715	1	A → T in MYOSCN4A. Ref.28		VAR_054940
	Natural variant	781	1	V → I in HYPP and NKPP. Ref.15 Ref.34		VAR_054941
	Natural variant	804	1	S → F in PMC. Ref.9		VAR_001563
	Natural variant	804	1	S → N in MYOSCN4A. Ref.28		VAR_054942
	Natural variant	861	1	A → D.		VAR_001564
	Natural variant	1129	1	R → Q in NKPP and HOKPP2; detected in a family where three affected members manifested hypokalemic periodic paralysis whereas five other patients had normokalemic periodic paralysis. Ref.42		VAR_064987
	Natural variant	1132	1	R → Q in HOKPP2. Ref.40		VAR_054943
	Natural variant	1135	1	R → H in HOKPP2. Ref.40		VAR_054944
	Natural variant	1152	1	A → D in PMC. Ref.27		VAR_022341
	Natural variant	1156	1	A → T in PMC, MYOSCN4A and HYPP. Ref.9 Ref.38		VAR_001565
	Natural variant	1158	1	P → S in HOKPP2. Ref.22		VAR_017792
	Natural variant	1160	1	I → V in MYOSCN4A; acetazolamide-responsive myotonia. Ref.14		VAR_017793
	Natural variant	1293	1	V → I in PMC; without cold paralysis. Ref.16		VAR_001566
	Natural variant	1297	1	N → K in MYOSCN4A; unusually severe and lethal phenotype with neonatal onset. Ref.33		VAR_054945
	Natural variant	1306	1	G → A in PMC. Ref.12 Ref.36		VAR_001567
	Natural variant	1306	1	G → E in MYOSCN4A and PMC; severe. Ref.12 Ref.29 Ref.36 Ref.38		VAR_001568
	Natural variant	1306	1	G → V in MYOSCN4A and PMC. Ref.6 Ref.12 Ref.39		VAR_001569
	Natural variant	1310	1	I → N in MYOSCN4A. Ref.28		VAR_054946
	Natural variant	1313	1	T → M in PMC. Ref.6 Ref.36		VAR_001570
	Natural variant	1376	1	N → D. Ref.1 Corresponds to variant rs2058194 [ dbSNP | Ensembl ].		VAR_017794
	Natural variant	1433	1	L → R in PMC and HYPP. Ref.11		VAR_001571
	Natural variant	1436	1	L → P in PMC. Ref.36		VAR_054947
	Natural variant	1442	1	V → E in CMSAR. Ref.3		VAR_017795
	Natural variant	1448	1	R → C in PMC. Ref.10 Ref.36		VAR_001572
	Natural variant	1448	1	R → H in PMC. Ref.10 Ref.36		VAR_001573
	Natural variant	1448	1	R → L in PMC. Ref.36		VAR_054948
	Natural variant	1456	1	G → E in PMC. Ref.18 Ref.21 Ref.36		VAR_037107
	Natural variant	1473	1	F → S in PMC; accelerates deactivation from the inactivated state and enhances the remobilization of gating charge. Ref.35 Ref.36		VAR_054949
	Natural variant	1476	1	M → I in MYOSCN4A; highly variable severity. Ref.32 Ref.39		VAR_054950
	Natural variant	1481	1	A → D in MYOSCN4A; fluctuating cold-induced and exercise-induced stiffness. Ref.31		VAR_054951
	Natural variant	1589	1	V → M in PMC. Ref.13 Ref.36		VAR_001574
	Natural variant	1592	1	M → V in HYPP and NKPP. Ref.8 Ref.34		VAR_001575
	Natural variant	1705	1	F → I in PMC; increases the extent of charge immobilization in response to strong depolarization. Ref.35		VAR_054952
Experimental info
	Sequence conflict	10 – 11	2	VP → AR in AAA60554. Ref.1
	Sequence conflict	371	1	E → K in AAA60554. Ref.1
	Sequence conflict	371	1	E → Q in AAB59624. Ref.1
	Sequence conflict	870	1	A → G in AAB59624. Ref.1
	Sequence conflict	1151 – 1152	2	NA → KP in AAB59624. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P35499 [UniParc]. Last modified March 23, 2010. Version 4. Checksum: FA9A6B81B7C2D50F	FASTA	1,836	208,061
	10 20 30 40 50 60 MARPSLCTLV PLGPECLRPF TRESLAAIEQ RAVEEEARLQ RNKQMEIEEP ERKPRSDLEA 70 80 90 100 110 120 GKNLPMIYGD PPPEVIGIPL EDLDPYYSNK KTFIVLNKGK AIFRFSATPA LYLLSPFSVV 130 140 150 160 170 180 RRGAIKVLIH ALFSMFIMIT ILTNCVFMTM SDPPPWSKNV EYTFTGIYTF ESLIKILARG 190 200 210 220 230 240 FCVDDFTFLR DPWNWLDFSV IMMAYLTEFV DLGNISALRT FRVLRALKTI TVIPGLKTIV 250 260 270 280 290 300 GALIQSVKKL SDVMILTVFC LSVFALVGLQ LFMGNLRQKC VRWPPPFNDT NTTWYSNDTW 310 320 330 340 350 360 YGNDTWYGNE MWYGNDSWYA NDTWNSHASW ATNDTFDWDA YISDEGNFYF LEGSNDALLC 370 380 390 400 410 420 GNSSDAGHCP EGYECIKTGR NPNYGYTSYD TFSWAFLALF RLMTQDYWEN LFQLTLRAAG 430 440 450 460 470 480 KTYMIFFVVI IFLGSFYLIN LILAVVAMAY AEQNEATLAE DKEKEEEFQQ MLEKFKKHQE 490 500 510 520 530 540 ELEKAKAAQA LEGGEADGDP AHGKDCNGSL DTSQGEKGAP RQSSSGDSGI SDAMEELEEA 550 560 570 580 590 600 HQKCPPWWYK CAHKVLIWNC CAPWLKFKNI IHLIVMDPFV DLGITICIVL NTLFMAMEHY 610 620 630 640 650 660 PMTEHFDNVL TVGNLVFTGI FTAEMVLKLI AMDPYEYFQQ GWNIFDSIIV TLSLVELGLA 670 680 690 700 710 720 NVQGLSVLRS FRLLRVFKLA KSWPTLNMLI KIIGNSVGAL GNLTLVLAII VFIFAVVGMQ 730 740 750 760 770 780 LFGKSYKECV CKIALDCNLP RWHMHDFFHS FLIVFRILCG EWIETMWDCM EVAGQAMCLT 790 800 810 820 830 840 VFLMVMVIGN LVVLNLFLAL LLSSFSADSL AASDEDGEMN NLQIAIGRIK LGIGFAKAFL 850 860 870 880 890 900 LGLLHGKILS PKDIMLSLGE ADGAGEAGEA GETAPEDEKK EPPEEDLKKD NHILNHMGLA 910 920 930 940 950 960 DGPPSSLELD HLNFINNPYL TIQVPIASEE SDLEMPTEEE TDTFSEPEDS KKPPQPLYDG 970 980 990 1000 1010 1020 NSSVCSTADY KPPEEDPEEQ AEENPEGEQP EECFTEACVQ RWPCLYVDIS QGRGKKWWTL 1030 1040 1050 1060 1070 1080 RRACFKIVEH NWFETFIVFM ILLSSGALAF EDIYIEQRRV IRTILEYADK VFTYIFIMEM 1090 1100 1110 1120 1130 1140 LLKWVAYGFK VYFTNAWCWL DFLIVDVSII SLVANWLGYS ELGPIKSLRT LRALRPLRAL 1150 1160 1170 1180 1190 1200 SRFEGMRVVV NALLGAIPSI MNVLLVCLIF WLIFSIMGVN LFAGKFYYCI NTTTSERFDI 1210 1220 1230 1240 1250 1260 SEVNNKSECE SLMHTGQVRW LNVKVNYDNV GLGYLSLLQV ATFKGWMDIM YAAVDSREKE 1270 1280 1290 1300 1310 1320 EQPQYEVNLY MYLYFVIFII FGSFFTLNLF IGVIIDNFNQ QKKKLGGKDI FMTEEQKKYY 1330 1340 1350 1360 1370 1380 NAMKKLGSKK PQKPIPRPQN KIQGMVYDLV TKQAFDITIM ILICLNMVTM MVETDNQSQL 1390 1400 1410 1420 1430 1440 KVDILYNINM IFIIIFTGEC VLKMLALRQY YFTVGWNIFD FVVVILSIVG LALSDLIQKY 1450 1460 1470 1480 1490 1500 FVSPTLFRVI RLARIGRVLR LIRGAKGIRT LLFALMMSLP ALFNIGLLLF LVMFIYSIFG 1510 1520 1530 1540 1550 1560 MSNFAYVKKE SGIDDMFNFE TFGNSIICLF EITTSAGWDG LLNPILNSGP PDCDPNLENP 1570 1580 1590 1600 1610 1620 GTSVKGDCGN PSIGICFFCS YIIISFLIVV NMYIAIILEN FNVATEESSE PLGEDDFEMF 1630 1640 1650 1660 1670 1680 YETWEKFDPD ATQFIAYSRL SDFVDTLQEP LRIAKPNKIK LITLDLPMVP GDKIHCLDIL 1690 1700 1710 1720 1730 1740 FALTKEVLGD SGEMDALKQT MEEKFMAANP SKVSYEPITT TLKRKHEEVC AIKIQRAYRR 1750 1760 1770 1780 1790 1800 HLLQRSMKQA SYMYRHSHDG SGDDAPEKEG LLANTMSKMY GHENGNSSSP SPEEKGEAGD 1810 1820 1830 AGPTMGLMPI SPSDTAWPPA PPPGQTVRPG VKESLV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Primary structure of the adult human skeletal muscle voltage-dependent sodium channel." George A.L. Jr., Komisarof J., Kallen R.G., Barchi R.L. Ann. Neurol. 31:131-137(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANTS GLY-524; ASP-559 AND ASP-1376. Tissue: Skeletal muscle.
[2]	"Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q." Wang J., Rojas C.V., Zhou J., Schwartz L.S., Nicholas H., Hoffmann E.P. Biochem. Biophys. Res. Commun. 182:794-801(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Myasthenic syndrome caused by mutation of the SCN4A sodium channel." Tsujino A., Maertens C., Ohno K., Shen X.-M., Fukuda T., Harper C.M., Cannon S.C., Engel A.G. Proc. Natl. Acad. Sci. U.S.A. 100:7377-7382(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CMSAR GLU-1442, VARIANTS LEU-246; GLY-524 AND ASP-559.
[4]	"The genomic structure of the human skeletal muscle sodium channel gene." McClatchey A.I., Lin C.S., Wang J., Hoffman E.P., Rojas C.V., Gusella J.F. Hum. Mol. Genet. 1:521-527(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLY-524.
[5]	"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage." Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C. Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita." McClatchey A.I., van den Bergh P., Pericak-Vance M.A., Raskind W., Verellen C., McKenna-Yasek D., Rao K., Haines J.L., Bird T., Brown R.H. Jr., Gusella J.F. Cell 68:769-774(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1305-1339, VARIANTS PMC VAL-1306 AND MET-1313.
[7]	"Identification of a mutation in the gene causing hyperkalemic periodic paralysis." Ptacek L.J., George A.L. Jr., Griggs R.C., Tawil R., Kallen R.G., Barchi R.L., Robertson M., Leppert M.F. Cell 67:1021-1027(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HYPP MET-704.
[8]	"A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis." Rojas C.V., Wang J., Schwartz L.S., Hoffman E.P., Powell B.R., Brown R.H. Jr. Nature 354:387-389(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HYPP VAL-1592.
[9]	"Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel." McClatchey A.I., McKenna-Yasek D., Cros D., Worthen H.G., Kuncl R.W., Desilva S.M., Cornblath D.R., Gusella J.F., Brown R.H. Jr. Nat. Genet. 2:148-152(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PMC PHE-804 AND THR-1156.
[10]	"Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita." Ptacek L.J., George A.L. Jr., Barchi R.L., Griggs R.C., Riggs J.E., Robertson M., Leppert M.F. Neuron 8:891-897(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PMC CYS-1448 AND HIS-1448.
[11]	"Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis." Ptacek L.J., Gouw L., Kwiecinski H., McManis P., Mendell J.R., Barohn R.J., George A.L. Jr., Barchi R.L., Robertson M., Leppert M.F. Ann. Neurol. 33:300-307(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC/HYPP ARG-1433.
[12]	"Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker." Lerche H., Heine R., Pika U., George A.L. Jr., Mitrovic N., Browatzki M., Weiss T., Rivet-Bastide M., Franke C., Lomonaco M., Ricker K., Lehmann-Horn F. J. Physiol. (Lond.) 470:13-22(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PMC ALA-1306; GLU-1306 AND VAL-1306.
[13]	"A novel SCN4A mutation causing myotonia aggravated by cold and potassium." Heine R., Pika U., Lehmann-Horn F. Hum. Mol. Genet. 2:1349-1353(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC MET-1589.
[14]	"Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis." Ptacek L.J., Tawil R., Griggs R.C., Meola G., McManis P., Barohn R.J., Mendell J.R., Harris C., Spitzer R., Santiago F., Leppert M.F. Neurology 44:1500-1503(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A VAL-1160.
[15]	"Hyperkalemic periodic paralysis with cardiac dysrhythmia: a novel sodium channel mutation?" Baquero J.L., Ayala R.A., Wang J., Curless R.G., Feero W.G., Hoffman E.P., Ebeid M.R. Ann. Neurol. 37:408-411(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HYPP ILE-781.
[16]	"Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile)." Koch M.C., Baumbach K., George A.L. Jr., Ricker K. NeuroReport 6:2001-2004(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC ILE-1293.
[17]	"A novel muscle sodium channel mutation causes painful congenital myotonia." Rosenfeld J., Sloan-Brown K., George A.L. Jr. Ann. Neurol. 42:811-814(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A MET-445.
[18]	"A novel mutation in the gene for the adult skeletal muscle sodium channel alpha-subunit (SCN4A) that causes paramyotonia congenita of von Eulenburg." Sasaki R., Takano H., Kamakura K., Kaida K., Hirata A., Saito M., Tanaka H., Kuzuhara S., Tsuji S. Arch. Neurol. 56:692-696(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC GLU-1456.
[19]	"Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia." Wang D.W., VanDeCarr D., Ruben P.C., George A.L. Jr., Bennett P.B. FEBS Lett. 448:231-234(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A MET-445.
[20]	"A novel sodium channel mutation in a family with hypokalemic periodic paralysis." Bulman D.E., Scoggan K.A., van Oene M.D., Nicolle M.W., Hahn A.F., Tollar L.L., Ebers G.C. Neurology 53:1932-1936(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HOKPP2 HIS-669.
[21]	"Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita." Davies N.P., Eunson L.H., Gregory R.P., Mills K.R., Morrison P.J., Hanna M.G. J. Neurol. Neurosurg. Psych. 68:504-507(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC GLU-1456.
[22]	"Temperature-sensitive sodium channelopathy with heat-induced myotonia and cold-induced paralysis." Sugiura Y., Aoki T., Sugiyama Y., Hida C., Ogata M., Yamamoto T. Neurology 54:2179-2181(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HOKPP2 SER-1158.
[23]	"Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current." Jurkat-Rott K., Mitrovic N., Hang C., Kouzmekine A., Iaizzo P., Herzog J., Lerche H., Nicole S., Vale-Santos J., Chauveau D., Fontaine B., Lehmann-Horn F. Proc. Natl. Acad. Sci. U.S.A. 97:9549-9554(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HOKPP2 GLY-672 AND HIS-672.
[24]	"Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis." Bendahhou S., Cummins T.R., Griggs R.C., Fu Y.H., Ptacek L.J. Ann. Neurol. 50:417-420(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HOKPP2 SER-672.
[25]	"Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK." Davies N.P., Eunson L.H., Samuel M., Hanna M.G. Neurology 57:1323-1325(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HOKPP2 SER-672.
[26]	"New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis." Vicart S., Sternberg D., Fournier E., Ochsner F., Laforet P., Kuntzer T., Eymard B., Hainque B., Fontaine B. Neurology 63:2120-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS NKPP GLY-675; GLN-675 AND TRP-675.
[27]	"A1152D mutation of the Na+ channel causes paramyotonia congenita and emphasizes the role of DIII/S4-S5 linker in fast inactivation." Bouhours M., Luce S., Sternberg D., Willer J.-C., Fontaine B., Tabti N. J. Physiol. (Lond.) 565:415-427(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC ASP-1152.
[28]	"Cold extends electromyography distinction between ion channel mutations causing myotonia." Fournier E., Viala K., Gervais H., Sternberg D., Arzel-Hezode M., Laforet P., Eymard B., Tabti N., Willer J.-C., Vial C., Fontaine B. Ann. Neurol. 60:356-365(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC LYS-270, VARIANTS MYOSCN4A THR-715; ASN-804 AND ASN-1310.
[29]	"Autosomal dominant monosymptomatic myotonia permanens." Colding-Joergensen E., Duno M., Vissing J. Neurology 67:153-155(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A GLU-1306.
[30]	"The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis." Kim J.-B., Kim M.-H., Lee S.J., Kim D.-J., Lee B.C. J. Korean Med. Sci. 22:946-951(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HOKPP2 HIS-669; CYS-672 AND GLY-672.
[31]	"A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene." Schoser B.G.H., Schroeder J.M., Grimm T., Sternberg D., Kress W. Muscle Nerve 35:599-606(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A ASP-1481.
[32]	"A novel founder SCN4A mutation causes painful cold-induced myotonia in French-Canadians." Rossignol E., Mathieu J., Thiffault I., Tetreault M., Dicaire M.J., Chrestian N., Dupre N., Puymirat J., Brais B. Neurology 69:1937-1941(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A ILE-1476.
[33]	"Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene." Gay S., Dupuis D., Faivre L., Masurel-Paulet A., Labenne M., Colombani M., Soichot P., Huet F., Hainque B., Sternberg D., Fontaine B., Gouyon J.B., Thauvin-Robinet C. Am. J. Med. Genet. A 146:380-383(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A LYS-1297.
[34]	"Mutations of sodium channel alpha-subunit genes in Chinese patients with normokalemic periodic paralysis." Xiuhai G., Weiping W., Ke Z., Hongbin W., Yiling S., Yanling M. Cell. Mol. Neurobiol. 28:653-661(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS NKPP GLN-675; ILE-781 AND VAL-1592.
[35]	"Differential effects of paramyotonia congenita mutations F1473S and F1705I on sodium channel gating." Groome J.R., Larsen M.F., Coonts A. Channels 2:39-50(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS PMC SER-1473 AND ILE-1705.
[36]	"What causes paramyotonia in the United Kingdom? Common and new SCN4A mutations revealed." Matthews E., Tan S.V., Fialho D., Sweeney M.G., Sud R., Haworth A., Stanley E., Cea G., Davis M.B., Hanna M.G. Neurology 70:50-53(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PMC LYS-270; MET-704; ALA-1306; GLU-1306; MET-1313; PRO-1436; CYS-1448; HIS-1448; LEU-1448; GLU-1456; SER-1473 AND MET-1589.
[37]	"A novel dominant mutation of the Nav1.4 alpha-subunit domain I leading to sodium channel myotonia." Petitprez S., Tiab L., Chen L., Kappeler L., Rosler K.M., Schorderet D., Abriel H., Burgunder J.M. Neurology 71:1669-1675(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MYOSCN4A VAL-141, CHARACTERIZATION OF VARIANT MYOSCN4A VAL-141.
[38]	"Clinical diversity of SCN4A-mutation-associated skeletal muscle sodium channelopathy." Lee S.C., Kim H.S., Park Y.E., Choi Y.C., Park K.H., Kim D.S. J. Clin. Neurol. 5:186-191(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MYOSCN4A TRP-225; THR-1156 AND GLU-1306, VARIANT PMC THR-693, VARIANT HYPP THR-1156.
[39]	"Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in French-Canadians." Dupre N., Chrestian N., Bouchard J.-P., Rossignol E., Brunet D., Sternberg D., Brais B., Mathieu J., Puymirat J. Neuromuscul. Disord. 19:330-334(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MYOSCN4A MET-445; LYS-452; SER-671; VAL-1306 AND ILE-1476.
[40]	"Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis." Matthews E., Labrum R., Sweeney M.G., Sud R., Haworth A., Chinnery P.F., Meola G., Schorge S., Kullmann D.M., Davis M.B., Hanna M.G. Neurology 72:1544-1547(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HOKPP2 TRP-222; CYS-672; GLY-672; HIS-672; SER-672; GLN-1132 AND HIS-1135.
[41]	"Tubular aggregates in paralysis periodica paramyotonica with T704M mutation of SCN4A." Luan X., Chen B., Liu Y., Zheng R., Zhang W., Yuan Y. Neuropathology 29:579-584(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PMC MET-704.
[42]	"Both hypokalaemic and normokalaemic periodic paralysis in different members of a single family with novel R1129Q mutation in SCN4A gene." Hong D., Luan X., Chen B., Zheng R., Zhang W., Wang Z., Yuan Y. J. Neurol. Neurosurg. Psych. 81:703-704(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT NKPP GLN-1129, VARIANT HOKPP2 GLN-1129.
[43]	"Hypokalemic periodic paralysis due to the SCN4A R672H mutation in a Turkish family." Incecik F., Herguner M.O., Altunbasak S., Lehman-Horn F. Turk. J. Pediatr. 52:409-410(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HOKPP2 HIS-672.
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

SCN4A entry

Cross-references

Sequence databases
EMBL GenBank DDBJ	M81758 mRNA. Translation: AAA60554.1. L04236 , L04216, L04217, L04218, L04219, L04220, L04221, L04222, L04223, L04224, L04225, L04226, L04227, L04228, L04229, L04230, L04231, L04232, L04233, L04234, L04235 Genomic DNA. Translation: AAB59624.1. AY212253 mRNA. Translation: AAO83647.1. L01983 , L01962, L01963, L01964, L01965, L01966, L01967, L01968, L01969, L01970, L01971, L01972, L01973, L01974, L01975, L01976, L01977, L01978, L01979, L01980, L01981, L01982 Genomic DNA. Translation: AAA75557.1. Sequence problems. AC127029 Genomic DNA. No translation available. S82622 Genomic DNA. Translation: AAB21450.2.
IPI	IPI00292393.
PIR	I51964. I54323. I64893. JS0648.
RefSeq	NP_000325.4. NM_000334.4.
UniGene	Hs.46038.
3D structure databases
ProteinModelPortal	P35499.
SMR	P35499. Positions 131-272, 588-802, 1027-1296, 1346-1599, 1602-1754.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000396320.
Protein family/group databases
TCDB	1.A.1.10.4. voltage-gated ion channel (VIC) superfamily.
PTM databases
PhosphoSite	P35499.
Polymorphism databases
DMDM	292495096.
Proteomic databases
PaxDb	P35499.
PRIDE	P35499.
Protocols and materials databases
DNASU	6329.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000435607; ENSP00000396320; ENSG00000007314.
GeneID	6329.
KEGG	hsa:6329.
UCSC	uc002jds.1. human.
Organism-specific databases
CTD	6329.
GeneCards	GC17M062015.
H-InvDB	HIX0039131.
HGNC	HGNC:10591. SCN4A.
HPA	HPA053992.
MIM	168300. phenotype. 170500. phenotype. 603967. gene. 608390. phenotype. 613345. phenotype. 614198. phenotype.
neXtProt	NX_P35499.
Orphanet	99736. Acetazolamide-responsive myotonia. 682. Hyperkalemic periodic paralysis. 681. Hypokalemic periodic paralysis. 99734. Myotonia fluctuans. 99735. Myotonia permanens. 684. Paramyotonia congenita of Von Eulenburg. 98913. Postsynaptic congenital myasthenic syndromes.
PharmGKB	PA35006.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG1226.
HOGENOM	HOG000231755.
HOVERGEN	HBG053100.
InParanoid	P35499.
KO	K04837.
OMA	IIRRGAI.
OrthoDB	EOG4B2SW8.
Enzyme and pathway databases
Reactome	REACT_111045. Developmental Biology.
Gene expression databases
ArrayExpress	P35499.
Bgee	P35499.
CleanEx	HS_SCN4A.
Genevestigator	P35499.
GermOnline	ENSG00000007314. Homo sapiens.
Family and domain databases
InterPro	IPR005821. Ion_trans_dom. IPR000048. IQ_motif_EF-hand-BS. IPR008052. Na_channel_a4su. IPR001696. Na_channel_asu. IPR010526. Na_trans_assoc. [Graphical view]
Pfam	PF00520. Ion_trans. 4 hits. PF06512. Na_trans_assoc. 1 hit. [Graphical view]
PRINTS	PR00170. NACHANNEL. PR01665. NACHANNEL4.
SMART	SM00015. IQ. 1 hit. [Graphical view]
PROSITE	PS50096. IQ. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChEMBL	CHEMBL2072.
DrugBank	DB00555. Lamotrigine.
GenomeRNAi	6329.
NextBio	24570.
SOURCE	Search...

Entry information

Entry name

SCN4A_HUMAN

Accession

Primary (citable) accession number: P35499
Secondary accession number(s): Q15478, Q16447, Q7Z6B1

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	March 23, 2010
Last modified:	May 1, 2013
This is version 136 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.