Reviewed, UniProtKB/Swiss-Prot P35523 (CLCN1_HUMAN)

Names and origin

Protein names

Recommended name:
    Chloride channel protein, skeletal muscle
Alternative name(s):
    Chloride channel protein 1
      Short name=ClC-1

Gene names

Name:	CLCN1
Synonyms:	CLC1

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	988 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport.
Subunit structure	Homotetramer Probable.
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Predominantly expressed in skeletal muscles.
Involvement in disease	Defects in CLCN1 are the cause of autosomal dominant myotonia congenita (MCD) [MIM:160800]; also known as Thomsen disease. MCD is characterized by skeletal muscle stiffness (delayed relaxation), due to membrane hyperexcitability. A variant form of Thomsen disease is myotonia levior that is characterized by milder symptoms, later onset and absence of muscle hypo- and hypertrophy. Ref.1 Ref.5 Ref.9 Ref.10 Ref.12 Ref.14 Defects in CLCN1 are the cause of autosomal recessive myotonia congenita (MCR) [MIM:255700]; also known as Becker disease. Ref.9 Ref.4 Ref.6 Ref.7 Ref.8 Ref.11 Ref.13
Miscellaneous	The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels.
Sequence similarities	Belongs to the chloride channel (TC 2.A.49) family. [View classification] Contains 2 CBS domains.

Ontologies

Keywords
Biological process	Ion transport Transport
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	CBS domain Repeat Transmembrane
Ligand	Chloride
Molecular function	Chloride channel Ionic channel Voltage-gated channel
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	muscle contraction Ref.4 Traceable author statement. Source: ProtInc
Cellular component	chloride channel complex Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Traceable author statement. Source: ProtInc
Molecular function	chloride ion binding Inferred from electronic annotation. Source: UniProtKB-KW voltage-gated chloride channel activity 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 – 988	988	Chloride channel protein, skeletal muscle		PRO_0000094429
Regions
	Topological domain	1 – 114	114	Cytoplasmic By similarity
	Transmembrane	115 – 152	38	By similarity
	Transmembrane	159 – 182	24	By similarity
	Transmembrane	207 – 225	19	By similarity
	Transmembrane	232 – 250	19	By similarity
	Transmembrane	302 – 321	20	By similarity
	Transmembrane	348 – 376	29	By similarity
	Transmembrane	385 – 404	20	By similarity
	Transmembrane	454 – 474	21	By similarity
	Transmembrane	482 – 505	24	By similarity
	Transmembrane	556 – 573	18	By similarity
	Topological domain	574 – 988	415	Cytoplasmic By similarity
	Domain	609 – 668	60	CBS 1
	Domain	821 – 876	56	CBS 2
	Region	191 – 198	8	In-membrane helix By similarity
	Region	266 – 278	13	In-membrane helix By similarity
	Region	282 – 290	9	In-membrane helix By similarity
	Region	522 – 536	15	In-membrane helix By similarity
	Region	537 – 538	2	In-membrane loop between two helices By similarity
	Region	539 – 550	12	In-membrane helix By similarity
	Region	551 – 555	5	In-membrane loop between two helices By similarity
	Motif	188 – 192	5	Selectivity filter part_1 By similarity
	Motif	230 – 234	5	Selectivity filter part_2 By similarity
	Motif	482 – 486	5	Selectivity filter part_3 By similarity
Sites
	Binding site	189	1	Chloride By similarity
	Binding site	484	1	Chloride; via amide nitrogen By similarity
	Binding site	578	1	Chloride By similarity
Natural variations
	Natural variant	105	1	R → C in MCR.		VAR_001582
	Natural variant	118	1	W → G: dbSNP rs10282312. Ref.10 Ref.2		VAR_001583
	Natural variant	136	1	D → G in MCR. Ref.7		VAR_001584
	Natural variant	150	1	Y → C in MCR. Ref.11		VAR_001585
	Natural variant	161	1	F → V in MCD and MCR. Ref.14		VAR_001586
	Natural variant	165	1	V → G in MCR.		VAR_001587
	Natural variant	167	1	F → L in MCR. Ref.8		VAR_001588
	Natural variant	200	1	G → R in MCD and MCR. Ref.11		VAR_001589
	Natural variant	230	1	G → E in MCD and MCR. Ref.5		VAR_001590
	Natural variant	236	1	V → L in MCR. Ref.12		VAR_001591
	Natural variant	261	1	Y → C in MCR. Ref.11		VAR_001592
	Natural variant	285	1	G → E in MCR. Ref.12		VAR_001593
	Natural variant	286	1	V → A in MCD. Ref.12		VAR_001594
	Natural variant	290	1	I → M in MCD. Ref.10		VAR_001595
	Natural variant	291	1	E → K in MCR.		VAR_001596
	Natural variant	300	1	R → Q		VAR_001597
	Natural variant	307	1	F → S in MCD. Ref.12		VAR_001598
	Natural variant	313	1	A → T in MCD and MCR. Ref.14		VAR_001599
	Natural variant	317	1	R → Q in MCD.		VAR_001600
	Natural variant	327	1	V → I in MCR.		VAR_001601
	Natural variant	329	1	I → T in MCR.		VAR_001602
	Natural variant	338	1	R → Q in MCD and MCR. Ref.8		VAR_001603
	Natural variant	413	1	F → C in MCR. Ref.4		VAR_001604
	Natural variant	415	1	A → V in MCR. Ref.11		VAR_001605
	Natural variant	437	1	A → T: dbSNP rs41276054.		VAR_001606
	Natural variant	480	1	P → L in MCD. Ref.1		VAR_001607
	Natural variant	482	1	G → R in MCR.		VAR_001608
	Natural variant	485	1	M → V in MCR. Ref.12		VAR_001609
	Natural variant	496	1	R → S in MCR. Ref.6		VAR_001610
	Natural variant	548	1	E → K in a breast cancer sample; somatic mutation. Ref.15		VAR_036300
	Natural variant	552	1	Q → R in MCD, MCR and in myotonia levior. Ref.10		VAR_001611
	Natural variant	556	1	I → N in MCD and MCR; mild form. Ref.12 Ref.14		VAR_001612
	Natural variant	563	1	V → I in MCR. Ref.13		VAR_001613
	Natural variant	708	1	F → L in MCR. Ref.13		VAR_001614
	Natural variant	727	1	P → L: dbSNP rs13438232.		VAR_047779
Experimental info
	Sequence conflict	697	1	L → P in CAA80996. Ref.1
	Sequence conflict	697	1	L → P in CAA81103. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P35523-1 [UniParc]. Last modified November 25, 2008. Version 2. Checksum: 088A71B4112182F7	FASTA	988	108,756
	10 20 30 40 50 60 MEQSRSQQRG GEQSWWGSDP QYQYMPFEHC TSYGLPSENG GLQHRLRKDA GPRHNVHPTQ 70 80 90 100 110 120 IYGHHKEQFS DREQDIGMPK KTGSSSTVDS KDEDHYSKCQ DCIHRLGQVV RRKLGEDWIF 130 140 150 160 170 180 LVLLGLLMAL VSWSMDYVSA KSLQAYKWSY AQMQPSLPLQ FLVWVTFPLV LILFSALFCH 190 200 210 220 230 240 LISPQAVGSG IPEMKTILRG VVLKEYLTMK AFVAKVVALT AGLGSGIPVG KEGPFVHIAS 250 260 270 280 290 300 ICAAVLSKFM SVFCGVYEQP YYYSDILTVG CAVGVGCCFG TPLGGVLFSI EVTSTYFAVR 310 320 330 340 350 360 NYWRGFFAAT FSAFVFRVLA VWNKDAVTIT ALFRTNFRMD FPFDLKELPA FAAIGICCGL 370 380 390 400 410 420 LGAVFVYLHR QVMLGVRKHK ALSQFLAKHR LLYPGIVTFV IASFTFPPGM GQFMAGELMP 430 440 450 460 470 480 REAISTLFDN NTWVKHAGDP ESLGQSAVWI HPRVNVVIII FLFFVMKFWM SIVATTMPIP 490 500 510 520 530 540 CGGFMPVFVL GAAFGRLVGE IMAMLFPDGI LFDDIIYKIL PGGYAVIGAA ALTGAVSHTV 550 560 570 580 590 600 STAVICFELT GQIAHILPMM VAVILANMVA QSLQPSLYDS IIQVKKLPYL PDLGWNQLSK 610 620 630 640 650 660 YTIFVEDIMV RDVKFVSASY TYGELRTLLQ TTTVKTLPLV DSKDSMILLG SVERSELQAL 670 680 690 700 710 720 LQRHLCPERR LRAAQEMARK LSELPYDGKA RLAGEGLPGA PPGRPESFAF VDEDEDEDLS 730 740 750 760 770 780 GKSELPPSLA LHPSTTAPLS PEEPNGPLPG HKQQPEAPEP AGQRPSIFQS LLHCLLGRAR 790 800 810 820 830 840 PTKKKTTQDS TDLVDNMSPE EIEAWEQEQL SQPVCFDSCC IDQSPFQLVE QTTLHKTHTL 850 860 870 880 890 900 FSLLGLHLAY VTSMGKLRGV LALEELQKAI EGHTKSGVQL RPPLASFRNT TSTRKSTGAP 910 920 930 940 950 960 PSSAENWNLP EDRPGATGTG DVIAASPETP VPSPSPEPPL SLAPGKVEGE LEELELVESP 970 980 GLEEELADIL QGPSLRSTDE EDEDELIL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen)." Steinmeyer K., Lorenz C., Pusch M., Koch M.C., Jentsch T.J. EMBO J. 13:737-743(1994) [PubMed: 8112288] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT MCD LEU-480.
[2]	"Human chromosome 7: DNA sequence and biology." Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C. Science 300:767-772(2003) [PubMed: 12690205] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT GLY-118.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"The skeletal muscle chloride channel in dominant and recessive human myotonia." Koch M.C., Steinmeyer K., Lorenz C., Ricker K., Wolf F., Otto M., Zoll B., Lehmann-Horn F., Grzeschik K.-H., Jentsch T.J. Science 257:797-800(1992) [PubMed: 1379744] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 171-988, VARIANT MCR CYS-413.
[5]	"Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita)." George A.L. Jr., Crackower M.A., Abdalla J.A., Hudson A.J., Ebers G.C. Nat. Genet. 3:305-310(1993) [PubMed: 7981750] [Abstract] Cited for: PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT MCD GLU-230.
[6]	"Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia." Lorenz C., Meyer-Kleine C., Steinmeyer K., Koch M.C., Jentsch T.J. Hum. Mol. Genet. 3:941-946(1994) [PubMed: 7951242] [Abstract] Cited for: VARIANT MCR SER-496.
[7]	"Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion." Heine R., George A.L. Jr., Pika U., Deymeer F., Ruedel R., Lehmann-Horn F. Hum. Mol. Genet. 3:1123-1128(1994) [PubMed: 7981681] [Abstract] Cited for: VARIANT MCR GLY-136.
[8]	"Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita." George A.L. Jr., Sloan-Brown K., Fenichel G.M., Mitchell G.A., Spiegel R., Pascuzzi R.M. Hum. Mol. Genet. 3:2071-2072(1994) [PubMed: 7874130] [Abstract] Cited for: VARIANTS MCR LEU-167 AND GLN-338, VARIANT GLN-300.
[9]	"Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia." Meyer-Kleine C., Steinmeyer K., Ricker K., Jentsch T.J., Koch M.C. Am. J. Hum. Genet. 57:1325-1334(1995) [PubMed: 8533761] [Abstract] Cited for: VARIANTS MCR AND MCD.
[10]	"Myotonia levior is a chloride channel disorder." Lehmann-Horn F., Mailaender V., Heine R., George A.L. Jr. Hum. Mol. Genet. 4:1397-1402(1995) [PubMed: 7581380] [Abstract] Cited for: VARIANT MCD MET-290, VARIANT MYOTONIA LEVIOR ARG-552, VARIANT GLY-118.
[11]	"Novel muscle chloride channel mutations and their effects on heterozygous carriers." Mailaender V., Heine R., Deymeer F., Lehmann-Horn F. Am. J. Hum. Genet. 58:317-324(1996) [PubMed: 8571958] [Abstract] Cited for: VARIANTS MCR CYS-150; ARG-200; CYS-261 AND VAL-415.
[12]	"ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence." Kubisch C., Schmidt-Rose T., Fontaine B., Bretag A.H., Jentsch T.J. Hum. Mol. Genet. 7:1753-1760(1998) [PubMed: 9736777] [Abstract] Cited for: VARIANTS MCD/MCR LEU-236; GLU-285; ALA-286; SER-307; VAL-485 AND ASN-556.
[13]	"Identification of five new mutations and three novel polymorphisms in the muscle chloride channel gene (CLCN1) in 20 Italian patients with dominant and recessive myotonia congenita." Sangiuolo F., Botta A., Mesoraca A., Servidei S., Merlini L., Fratta G., Novelli G., Dallapiccola B. Hum. Mutat. 11:331-331(1998) [PubMed: 10215406] [Abstract] Cited for: VARIANTS MCR ILE-563 AND LEU-708.
[14]	"Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance." Plassart-Schiess E., Gervais A., Eymard B., Lagueny A., Pouget J., Warter J.-M., Fardeau M., Jentsch T.J., Fontaine B. Neurology 50:1176-1179(1998) [PubMed: 9566422] [Abstract] Cited for: VARIANTS MCD/MCR VAL-161; THR-313 AND ASN-556.
[15]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] LYS-548.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	Z25587 Genomic DNA. Translation: CAA80996.1. Z25884 mRNA. Translation: CAA81103.1. CH236959 Genomic DNA. Translation: EAL23786.1. BC112156 mRNA. Translation: AAI12157.1. BC113495 mRNA. Translation: AAI13496.1. M97820 mRNA. No translation available. L08261 Genomic DNA. No translation available. L08262 Genomic DNA. No translation available. L08263 Genomic DNA. No translation available. L08264 Genomic DNA. No translation available. L08265 Genomic DNA. No translation available. Z25753 , Z25754, Z25755, Z25756, Z25757, Z25758, Z25759, Z25760, Z25761, Z25762, Z25763, Z25764, Z25765, Z25766, Z25767, Z25752 Genomic DNA. Translation: CAB56792.1. Z25768, Z25872 Genomic DNA. Translation: CAB56814.1.
IPI	IPI00293558.
PIR	S37078.
RefSeq	NP_000074.2.
UniGene	Hs.121483
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	P35523.
Protein family/group databases
TCDB	2.A.49.2.1. chloride carrier/channel (ClC) family.
PTM databases
PhosphoSite	P35523.
Genome annotation databases
Ensembl	ENST00000343257; ENSP00000339867; ENSG00000188037; Homo sapiens. [Genome view] ENST00000432192; ENSP00000395949; ENSG00000188037; Homo sapiens. [Genome view] ENST00000455478; ENSP00000400027; ENSG00000188037; Homo sapiens. [Genome view]
GeneID	1180.
KEGG	hsa:1180.
UCSC	uc003wcr.1. human.
Organism-specific databases
CTD	1180.
GeneCards	GC07P142723.
H-InvDB	HIX0033595.
HGNC	HGNC:2019. CLCN1.
MIM	118425. gene. 160800. phenotype. 255700. phenotype.
Orphanet	614. Thomsen and Becker disease.
PharmGKB	PA26546.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	P35523.
Gene expression databases
ArrayExpress	P35523.
Bgee	P35523.
CleanEx	HS_CLCN1.
Genevestigator	P35523.
GermOnline	ENSG00000188037. Homo sapiens.
Family and domain databases
InterPro	IPR014743. Cl-channel_core. IPR001807. Cl-channel_volt. IPR002243. Cl_channel1. IPR000644. Cysta_beta_synth_core. [Graphical view]
Gene3D	G3DSA:1.10.3080.10. Cl-channel_core. 1 hit.
PANTHER	PTHR11689. Cl-channel_volt. 1 hit.
Pfam	PF00571. CBS. 1 hit. PF00654. Voltage_CLC. 1 hit. [Graphical view]
PRINTS	PR00762. CLCHANNEL. PR01112. CLCHANNEL1.
PROSITE	PS51371. CBS. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

CLCN1_HUMAN

Accession

Primary (citable) accession number: P35523
Secondary accession number(s): A4D2H5, Q2M202

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	November 25, 2008
Last modified:	October 13, 2009
This is version 97 of the entry and version 2 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.