Reviewed, UniProtKB/Swiss-Prot P35499 (SCN4A_HUMAN)

Names and origin

Protein names

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

Gene names

Name:

SCN4A

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1836 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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	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. Ref.5 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.15 Ref.17 Ref.20 Ref.26 Ref.27 Ref.34 Ref.35 Ref.39 Defects in SCN4A are a cause of periodic paralysis hypokalemic (HOKPP) [MIM:170400]; also designated HYPOPP. HOKPP is an autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. Ref.19 Ref.21 Ref.22 Ref.23 Ref.24 Ref.29 Ref.38 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. Ref.6 Ref.7 Ref.14 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. 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. Ref.27 Ref.13 Ref.16 Ref.18 Ref.28 Ref.30 Ref.31 Ref.32 Ref.36 Ref.37 Defects in SCN4A are the cause of a congenital myasthenic syndrome due to mutation in SCNA4 (CMSSCNA4) [MIM:603967]. CMSSCNA4 is 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. Ref.3
Sequence similarities	Belongs to the sodium channel family. 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
Ligand	Sodium
Molecular function	Ionic channel Sodium channel Voltage-gated channel
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	muscle contraction Ref.8 Traceable author statement. Source: ProtInc sodium ion transport Ref.18 Traceable author statement. Source: ProtInc
Cellular component	voltage-gated sodium channel complex Inferred from electronic annotation. Source: InterPro
Molecular function	sodium ion binding Inferred from electronic annotation. Source: UniProtKB-KW voltage-gated sodium channel activity Ref.18 Traceable author statement. 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	S1 of repeat I Potential
	Transmembrane	159 – 178	20	S2 of repeat I Potential
	Transmembrane	191 – 210	20	S3 of repeat I Potential
	Transmembrane	217 – 236	20	S4 of repeat I Potential
	Transmembrane	253 – 266	14	S5 of repeat I Potential
	Transmembrane	424 – 449	26	S6 of repeat I Potential
	Transmembrane	574 – 597	24	S1 of repeat II Potential
	Transmembrane	609 – 632	24	S2 of repeat II Potential
	Transmembrane	641 – 660	20	S3 of repeat II Potential
	Transmembrane	667 – 686	20	S4 of repeat II Potential
	Transmembrane	702 – 724	23	S5 of repeat II Potential
	Transmembrane	777 – 802	26	S6 of repeat II Potential
	Transmembrane	1027 – 1049	23	S1 of repeat III Potential
	Transmembrane	1064 – 1089	26	S2 of repeat III Potential
	Transmembrane	1096 – 1116	21	S3 of repeat III Potential
	Transmembrane	1122 – 1143	22	S4 of repeat III Potential
	Transmembrane	1163 – 1184	22	S5 of repeat III Potential
	Transmembrane	1269 – 1295	27	S6 of repeat III Potential
	Transmembrane	1349 – 1372	24	S1 of repeat IV Potential
	Transmembrane	1384 – 1407	24	S2 of repeat IV Potential
	Transmembrane	1414 – 1437	24	S3 of repeat IV Potential
	Transmembrane	1447 – 1469	23	S4 of repeat IV Potential
	Transmembrane	1485 – 1507	23	S5 of repeat IV Potential
	Transmembrane	1574 – 1598	25	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.36		VAR_054934
	Natural variant	222	1	R → W in HOKPP. Ref.38		VAR_054935
	Natural variant	246	1	S → L		VAR_017785
	Natural variant	270	1	Q → K in PMC. Ref.27 Ref.35		VAR_054936
	Natural variant	445	1	V → M in MYOSCN4A. Ref.16 Ref.18 Ref.37		VAR_017786
	Natural variant	452	1	E → K in MYOSCN4A; variable phenotype ranging from mild to severe myotonia. Ref.37		VAR_054937
	Natural variant	524	1	G → S		VAR_001561
	Natural variant	559	1	N → D: dbSNP rs1047705. Ref.3 Ref.1		VAR_017787
	Natural variant	669	1	R → H in HOKPP. Ref.19 Ref.29		VAR_017788
	Natural variant	671	1	F → S in MYOSCN4A. Ref.37		VAR_054938
	Natural variant	672	1	R → C in HOKPP. Ref.29 Ref.38		VAR_054939
	Natural variant	672	1	R → G in HOKPP. Ref.22 Ref.29 Ref.38		VAR_017789
	Natural variant	672	1	R → H in HOKPP. Ref.22 Ref.38		VAR_017790
	Natural variant	672	1	R → S in HOKPP. Ref.23 Ref.24 Ref.38		VAR_017791
	Natural variant	675	1	R → G in NKPP. Ref.25		VAR_037104
	Natural variant	675	1	R → Q in NKPP. Ref.25 Ref.33		VAR_037105
	Natural variant	675	1	R → W in NKPP. Ref.25		VAR_037106
	Natural variant	704	1	T → M in HYPP and PMC. Ref.35 Ref.39 Ref.6		VAR_001562
	Natural variant	715	1	A → T in MYOSCN4A. Ref.27		VAR_054940
	Natural variant	781	1	V → I in HYPP and NKPP. Ref.14 Ref.33		VAR_054941
	Natural variant	804	1	S → F in PMC. Ref.8		VAR_001563
	Natural variant	804	1	S → N in MYOSCN4A. Ref.27		VAR_054942
	Natural variant	861	1	A → D		VAR_001564
	Natural variant	1132	1	R → Q in HOKPP. Ref.38		VAR_054943
	Natural variant	1135	1	R → H in HOKPP. Ref.38		VAR_054944
	Natural variant	1152	1	A → D in PMC. Ref.26		VAR_022341
	Natural variant	1156	1	A → T in PMC and HYPP. Ref.8		VAR_001565
	Natural variant	1158	1	P → S in HOKPP. Ref.21		VAR_017792
	Natural variant	1160	1	I → V in MYOSCN4A; acetazolamide-responsive myotonia. Ref.13		VAR_017793
	Natural variant	1293	1	V → I in PMC; without cold paralysis. Ref.15		VAR_001566
	Natural variant	1297	1	N → K in MYOSCN4A; unusually severe and lethal phenotype with neonatal onset. Ref.32		VAR_054945
	Natural variant	1306	1	G → A in PMC. Ref.11 Ref.35		VAR_001567
	Natural variant	1306	1	G → E in MYOSCN4A and PMC; severe. Ref.11 Ref.35 Ref.28		VAR_001568
	Natural variant	1306	1	G → V in MYOSCN4A and PMC. Ref.5 Ref.11 Ref.37		VAR_001569
	Natural variant	1310	1	I → N in MYOSCN4A. Ref.27		VAR_054946
	Natural variant	1313	1	T → M in PMC. Ref.5 Ref.35		VAR_001570
	Natural variant	1376	1	D → N: dbSNP rs2058194. Ref.3 Ref.4		VAR_017794
	Natural variant	1433	1	L → R in PMC and HYPP. Ref.10		VAR_001571
	Natural variant	1436	1	L → P in PMC. Ref.35		VAR_054947
	Natural variant	1442	1	V → E in CMSSCNA4. Ref.3		VAR_017795
	Natural variant	1448	1	R → C in PMC. Ref.9 Ref.35		VAR_001572
	Natural variant	1448	1	R → H in PMC. Ref.9 Ref.35		VAR_001573
	Natural variant	1448	1	R → L in PMC. Ref.35		VAR_054948
	Natural variant	1456	1	G → E in PMC. Ref.17 Ref.20 Ref.35		VAR_037107
	Natural variant	1473	1	F → S in PMC; accelerates deactivation from the inactivated state and enhances the remobilization of gating charge. Ref.34 Ref.35		VAR_054949
	Natural variant	1476	1	M → I in MYOSCN4A; highly variable severity. Ref.31 Ref.37		VAR_054950
	Natural variant	1481	1	A → D in MYOSCN4A; fluctuating cold-induced and exercise-induced stiffness. Ref.30		VAR_054951
	Natural variant	1589	1	V → M in PMC. Ref.12 Ref.35		VAR_001574
	Natural variant	1592	1	M → V in HYPP and NKPP. Ref.7 Ref.33		VAR_001575
	Natural variant	1705	1	F → I in PMC; increases the extent of charge immobilization in response to strong depolarization. Ref.34		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)
	P35499-1 [UniParc]. Last modified March 1, 2004. Version 3. Checksum: 202BA3EE1EA244CD	FASTA	1,836	208,032
	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 RQSGSGDSGI 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 MVETDDQSQL 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

[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: 1315496] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT ASP-559. 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: 1310396] [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: 12766226] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CMSSCNA4 GLU-1442, VARIANTS LEU-246; ASP-559 AND ASN-1376.
[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: 1339144] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ASN-1376.
[5]	"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: 1310898] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1305-1339, VARIANTS PMC VAL-1306 AND MET-1313.
[6]	"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: 1659948] [Abstract] Cited for: VARIANT HYPP MET-704.
[7]	"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: 1659668] [Abstract] Cited for: VARIANT HYPP VAL-1592.
[8]	"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: 1338909] [Abstract] Cited for: VARIANTS PMC PHE-804 AND THR-1156.
[9]	"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: 1316765] [Abstract] Cited for: VARIANTS PMC CYS-1448 AND HIS-1448.
[10]	"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: 8388676] [Abstract] Cited for: VARIANT PMC/HYPP ARG-1433.
[11]	"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: 8308722] [Abstract] Cited for: VARIANTS PMC ALA-1306; GLU-1306 AND VAL-1306.
[12]	"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: 8242056] [Abstract] Cited for: VARIANT PMC MET-1589.
[13]	"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: 8058156] [Abstract] Cited for: VARIANT MYOSCN4A VAL-1160.
[14]	"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: 7695243] [Abstract] Cited for: VARIANT HYPP ILE-781.
[15]	"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: 8580427] [Abstract] Cited for: VARIANT PMC ILE-1293.
[16]	"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: 9392583] [Abstract] Cited for: VARIANT MYOSCN4A MET-445.
[17]	"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: 10369308] [Abstract] Cited for: VARIANT PMC GLU-1456.
[18]	"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: 10218481] [Abstract] Cited for: VARIANT MYOSCN4A MET-445.
[19]	"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: 10599760] [Abstract] Cited for: VARIANT HOKPP HIS-669.
[20]	"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: 10727489] [Abstract] Cited for: VARIANT PMC GLU-1456.
[21]	"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: 10851391] [Abstract] Cited for: VARIANT HOKPP SER-1158.
[22]	"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: 10944223] [Abstract] Cited for: VARIANTS HOKPP GLY-672 AND HIS-672.
[23]	"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: 11558801] [Abstract] Cited for: VARIANT HOKPP SER-672.
[24]	"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: 11591859] [Abstract] Cited for: VARIANT HOKPP SER-672.
[25]	"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: 15596759] [Abstract] Cited for: VARIANTS NKPP GLY-675; GLN-675 AND TRP-675.
[26]	"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: 15790667] [Abstract] Cited for: VARIANT PMC ASP-1152.
[27]	"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: 16786525] [Abstract] Cited for: VARIANT PMC LYS-270, VARIANTS MYOSCN4A THR-715; ASN-804 AND ASN-1310.
[28]	"Autosomal dominant monosymptomatic myotonia permanens." Colding-Joergensen E., Duno M., Vissing J. Neurology 67:153-155(2006) [PubMed: 16832098] [Abstract] Cited for: VARIANT MYOSCN4A GLU-1306.
[29]	"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: 18162704] [Abstract] Cited for: VARIANTS HOKPP HIS-669; CYS-672 AND GLY-672.
[30]	"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: 17212350] [Abstract] Cited for: VARIANT MYOSCN4A ASP-1481.
[31]	"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: 17998485] [Abstract] Cited for: VARIANT MYOSCN4A ILE-1476.
[32]	"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: 18203179] [Abstract] Cited for: VARIANT MYOSCN4A LYS-1297.
[33]	"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: 18046642] [Abstract] Cited for: VARIANTS NKPP GLN-675; ILE-781 AND VAL-1592.
[34]	"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: 18690054] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS PMC SER-1473 AND ILE-1705.
[35]	"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: 18166706] [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.
[36]	"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: 19015483] [Abstract] Cited for: VARIANT MYOSCN4A VAL-141, CHARACTERIZATION OF VARIANT MYOSCN4A VAL-141.
[37]	"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: 18337100] [Abstract] Cited for: VARIANTS MYOSCN4A MET-445; LYS-452; SER-671; VAL-1306 AND ILE-1476.
[38]	"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: 19118277] [Abstract] Cited for: VARIANTS HOKPP TRP-222; CYS-672; GLY-672; HIS-672; SER-672; GLN-1132 AND HIS-1135.
[39]	"Tubular aggregates in paralysis periodica paramyotonica with T704M mutation of SCN4A." Luan X., Chen B., Liu Y., Zheng R., Zhang W., Yuan Y. Neuropathology 0:0-0(2009) [PubMed: 19077043] [Abstract] Cited for: VARIANT PMC MET-704.
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

SCN4A entry

Cross-references

Sequence databases
EMBLGenBankDDBJ	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. S82622 Genomic DNA. Translation: AAB21450.2.
IPI	IPI00292393.
PIR	I51964. I54323. I64893. JS0648.
RefSeq	NP_000325.4.
UniGene	Hs.46038
3D structure databases
HSSP	HSSP built from PDB template 1QG9 based on UniProtKB P08104.
ModBase	Search...
Protein-protein interaction databases
STRING	P35499.
Protein family/group databases
TCDB	1.A.1.10.4. voltage-gated ion channel (VIC) superfamily.
Proteomic databases
PRIDE	P35499.
Genome annotation databases
Ensembl	ENST00000006839; ENSP00000006839; ENSG00000007314; Homo sapiens. [Genome view] ENST00000435607; ENSP00000396320; ENSG00000007314; Homo sapiens. [Genome view]
GeneID	6329.
KEGG	hsa:6329.
UCSC	uc002jds.1. human.
Organism-specific databases
CTD	6329.
GeneCards	GC17M059369.
HGNC	HGNC:10591. SCN4A.
MIM	168300. phenotype. 170400. phenotype. 170500. phenotype. 603967. gene+phenotype. 608390. phenotype.
Orphanet	590. Congenital myasthenic syndromes. 682. Hyperkalemic periodic paralysis. 681. Hypokalemic periodic paralysis. 99736. Myotonia congenita acetazolamide responsive. 99734. Myotonia fluctuans. 99735. Myotonia permanens. 684. Paramyotonia congenita of Von Eulenburg. 98913. Postsynaptic congenital myasthenic syndromes. 612. Potassium aggravated myotonia.
PharmGKB	PA35006.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P35499.
HOVERGEN	P35499.
Gene expression databases
ArrayExpress	P35499.
Bgee	P35499.
CleanEx	HS_SCN4A.
Genevestigator	P35499.
GermOnline	ENSG00000007314. Homo sapiens.
Family and domain databases
InterPro	IPR005821. Ion_trans. IPR000048. IQ_CaM_bd_region. IPR001696. Na_channel. IPR008052. Na_channel4. IPR010526. Na_trans_assoc. [Graphical view]
Pfam	PF00520. Ion_trans. 4 hits. PF00612. IQ. 1 hit. 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 Resources
DrugBank	DB00555. Lamotrigine.
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 1, 2004
Last modified:	October 13, 2009
This is version 101 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.