CLCN2_HUMAN
ID CLCN2_HUMAN Reviewed; 898 AA.
AC P51788; B4DQT9; B4DZ58; E9PBD9; E9PCD2; O14864; Q6IPA9; Q8WU13;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 09-FEB-2010, sequence version 2.
DT 03-AUG-2022, entry version 197.
DE RecName: Full=Chloride channel protein 2;
DE Short=ClC-2;
GN Name=CLCN2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT SER-668.
RC TISSUE=Placenta;
RX PubMed=7795595; DOI=10.1093/hmg/4.3.407;
RA Cid L.P., Montrose-Rafizadeh C., Smith D.I., Guggino W.B., Cutting G.R.;
RT "Cloning of a putative human voltage-gated chloride channel (ClC-2) cDNA
RT widely expressed in human tissues.";
RL Hum. Mol. Genet. 4:407-413(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lens epithelium;
RA Rae J.L., Shepard A.R.;
RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5), AND VARIANT
RP SER-668.
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Lung, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP TISSUE SPECIFICITY.
RC TISSUE=Aortic endothelium, and Vascular smooth muscle;
RX PubMed=10198195; DOI=10.1006/jmcc.1998.0901;
RA Lamb F.S., Clayton G.H., Liu B.-X., Smith R.L., Barna T.J., Schutte B.C.;
RT "Expression of CLCN voltage-gated chloride channel genes in human blood
RT vessels.";
RL J. Mol. Cell. Cardiol. 31:657-666(1999).
RN [7]
RP FUNCTION.
RX PubMed=19153159; DOI=10.1113/jphysiol.2008.167353;
RA Niemeyer M.I., Cid L.P., Yusef Y.R., Briones R., Sepulveda F.V.;
RT "Voltage-dependent and -independent titration of specific residues accounts
RT for complex gating of a ClC chloride channel by extracellular protons.";
RL J. Physiol. (Lond.) 587:1387-1400(2009).
RN [8]
RP RETRACTED PAPER.
RX PubMed=12612585; DOI=10.1038/ng1121;
RA Haug K., Warnstedt M., Alekov A.K., Sander T., Ramirez A., Poser B.,
RA Maljevic S., Hebeisen S., Kubisch C., Rebstock J., Horvath S., Hallmann K.,
RA Dullinger J.S., Rau B., Haverkamp F., Beyenburg S., Schulz H., Janz D.,
RA Giese B., Mueller-Newen G., Propping P., Elger C.E., Fahlke C., Lerche H.,
RA Heils A.;
RT "Mutations in CLCN2 encoding a voltage-gated chloride channel are
RT associated with idiopathic generalized epilepsies.";
RL Nat. Genet. 33:527-532(2003).
RN [9]
RP RETRACTION NOTICE OF PUBMED:12612585.
RX PubMed=19710717; DOI=10.1038/ng0909-1043;
RA Haug K., Warnstedt M., Alekov A.K., Sander T., Ramirez A., Poser B.,
RA Maljevic S., Hebeisen S., Kubisch C., Rebstock J., Horvath S., Hallmann K.,
RA Dullinger J.S., Rau B., Haverkamp F., Beyenburg S., Schulz H., Janz D.,
RA Giese B., Mueller-Newen G., Propping P., Elger C.E., Fahlke C., Lerche H.;
RL Nat. Genet. 41:1043-1043(2009).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-712, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [12]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INVOLVEMENT IN HALD2,
RP VARIANTS HALD2 LYS-22; ASN-26; GLN-172; LYS-362 DEL AND ARG-865, AND
RP CHARACTERIZATION OF VARIANTS HALD2 LYS-22; ASN-26; GLN-172; LYS-362 DEL AND
RP ARG-865.
RX PubMed=29403011; DOI=10.1038/s41588-018-0048-5;
RA Scholl U.I., Stoelting G., Schewe J., Thiel A., Tan H., Nelson-Williams C.,
RA Vichot A.A., Jin S.C., Loring E., Untiet V., Yoo T., Choi J., Xu S., Wu A.,
RA Kirchner M., Mertins P., Rump L.C., Onder A.M., Gamble C., McKenney D.,
RA Lash R.W., Jones D.P., Chune G., Gagliardi P., Choi M., Gordon R.,
RA Stowasser M., Fahlke C., Lifton R.P.;
RT "CLCN2 chloride channel mutations in familial hyperaldosteronism type II.";
RL Nat. Genet. 50:349-354(2018).
RN [13]
RP FUNCTION, INVOLVEMENT IN HALD2, VARIANT HALD2 ASP-24, AND CHARACTERIZATION
RP OF VARIANT HALD2 ASP-24.
RX PubMed=29403012; DOI=10.1038/s41588-018-0053-8;
RA Fernandes-Rosa F.L., Daniil G., Orozco I.J., Goeppner C., El Zein R.,
RA Jain V., Boulkroun S., Jeunemaitre X., Amar L., Lefebvre H.,
RA Schwarzmayr T., Strom T.M., Jentsch T.J., Zennaro M.C.;
RT "A gain-of-function mutation in the CLCN2 chloride channel gene causes
RT primary aldosteronism.";
RL Nat. Genet. 50:355-361(2018).
RN [14]
RP VARIANTS ARG-48; HIS-68; ALA-199; GLN-646; SER-668; TRP-725 AND HIS-747,
RP AND CHARACTERIZATION OF VARIANTS ARG-48; HIS-68; ALA-199; GLN-646; TRP-725
RP AND HIS-747.
RX PubMed=17762171; DOI=10.1159/000107528;
RA Paul J., Jeyaraj S., Huber S.M., Seebohm G., Boehmer C., Lang F.,
RA Kremsner P.G., Kun J.F.J.;
RT "Alterations in the cytoplasmic domain of CLCN2 result in altered gating
RT kinetics.";
RL Cell. Physiol. Biochem. 20:441-454(2007).
RN [15]
RP VARIANT LEU-719.
RX PubMed=19200853; DOI=10.1016/j.brainresbull.2009.01.008;
RA Combi R., Grioni D., Contri M., Redaelli S., Redaelli F., Bassi M.T.,
RA Barisani D., Lavitrano M.L., Tredici G., Tenchini M.L., Bertolini M.,
RA Dalpra L.;
RT "Clinical and genetic familial study of a large cohort of Italian children
RT with idiopathic epilepsy.";
RL Brain Res. Bull. 79:89-96(2009).
RN [16]
RP VARIANT JAE2 GLU-715, AND POSSIBLE INVOLVEMENT IN JAE2.
RX PubMed=19710712; DOI=10.1038/ng0909-954;
RA Kleefuss-Lie A., Friedl W., Cichon S., Haug K., Warnstedt M., Alekov A.,
RA Sander T., Ramirez A., Poser B., Maljevic S., Hebeisen S., Kubisch C.,
RA Rebstock J., Horvath S., Hallmann K., Dullinger J.S., Rau B., Haverkamp F.,
RA Beyenburg S., Schulz H., Janz D., Giese B., Muller-Newen G., Propping P.,
RA Elger C.E., Fahlke C., Lerche H.;
RT "CLCN2 variants in idiopathic generalized epilepsy.";
RL Nat. Genet. 41:954-955(2009).
RN [17]
RP INVOLVEMENT IN EJM8, INVOLVEMENT IN EIG11, VARIANT EJM8 GLN-235, VARIANT
RP EIG11 GLN-577, VARIANT CYS-644, CHARACTERIZATION OF VARIANT EJM8 GLN-235,
RP CHARACTERIZATION OF VARIANT EIG11 GLN-577, CHARACTERIZATION OF VARIANT
RP CYS-644, AND FUNCTION.
RX PubMed=19191339; DOI=10.1002/humu.20876;
RA Saint-Martin C., Gauvain G., Teodorescu G., Gourfinkel-An I., Fedirko E.,
RA Weber Y.G., Maljevic S., Ernst J.-P., Garcia-Olivares J., Fahlke C.,
RA Nabbout R., LeGuern E., Lerche H., Christophe Poncer J., Depienne C.;
RT "Two novel CLCN2 mutations accelerating chloride channel deactivation are
RT associated with idiopathic generalized epilepsy.";
RL Hum. Mutat. 30:397-405(2009).
RN [18]
RP VARIANTS LKPAT 144-LEU-ILE-145 DEL AND VAL-500, AND CHARACTERIZATION OF
RP VARIANTS LKPAT 144-LEU-ILE-145 DEL AND VAL-500.
RX PubMed=23707145; DOI=10.1016/s1474-4422(13)70053-x;
RA Depienne C., Bugiani M., Dupuits C., Galanaud D., Touitou V., Postma N.,
RA van Berkel C., Polder E., Tollard E., Darios F., Brice A.,
RA de Die-Smulders C.E., Vles J.S., Vanderver A., Uziel G., Yalcinkaya C.,
RA Frints S.G., Kalscheuer V.M., Klooster J., Kamermans M., Abbink T.E.,
RA Wolf N.I., Sedel F., van der Knaap M.S.;
RT "Brain white matter oedema due to ClC-2 chloride channel deficiency: an
RT observational analytical study.";
RL Lancet Neurol. 12:659-668(2013).
CC -!- FUNCTION: Voltage-gated chloride channel. Chloride channels have
CC several functions including the regulation of cell volume, membrane
CC potential stabilization, signal transduction and transepithelial
CC transport. Involved in the regulation of aldosterone production. The
CC opening of CLCN2 channels at hyperpolarized membrane potentials in the
CC glomerulosa causes cell membrane depolarization, activation of voltage-
CC gated Ca2+ channels and increased expression of aldosterone synthase,
CC the rate-limiting enzyme for aldosterone biosynthesis (PubMed:29403011,
CC PubMed:29403012). {ECO:0000269|PubMed:19153159,
CC ECO:0000269|PubMed:19191339, ECO:0000269|PubMed:29403011,
CC ECO:0000269|PubMed:29403012}.
CC -!- INTERACTION:
CC P51788-4; Q9UMX0-2: UBQLN1; NbExp=3; IntAct=EBI-16431116, EBI-10173939;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:29403011};
CC Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=P51788-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P51788-2; Sequence=VSP_007831, VSP_007832, VSP_036455;
CC Name=3;
CC IsoId=P51788-3; Sequence=VSP_036456;
CC Name=4;
CC IsoId=P51788-4; Sequence=VSP_045457;
CC Name=5;
CC IsoId=P51788-5; Sequence=VSP_045458;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Moderately expressed in
CC aortic and coronary vascular smooth muscle cells and expressed at a low
CC level in aortic endothelial cells. Expressed in the adrenal gland,
CC predominantly in the zona glomerulosa (PubMed:29403011).
CC {ECO:0000269|PubMed:10198195, ECO:0000269|PubMed:29403011}.
CC -!- PTM: Phosphorylated. Activated by dephosphorylation.
CC {ECO:0000250|UniProtKB:P35525}.
CC -!- DISEASE: Epilepsy, idiopathic generalized 11 (EIG11) [MIM:607628]: A
CC disorder characterized by recurring generalized seizures in the absence
CC of detectable brain lesions and/or metabolic abnormalities. Generalized
CC seizures arise diffusely and simultaneously from both hemispheres of
CC the brain. {ECO:0000269|PubMed:19191339}. Note=Disease susceptibility
CC is associated with variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Juvenile absence epilepsy 2 (JAE2) [MIM:607628]: A subtype of
CC idiopathic generalized epilepsy characterized by onset occurring around
CC puberty, absence seizures, generalized tonic-clonic seizures (GTCS),
CC GTCS on awakening, and myoclonic seizures.
CC {ECO:0000269|PubMed:19710712}. Note=Disease susceptibility may be
CC associated with variants affecting the gene represented in this entry.
CC -!- DISEASE: Juvenile myoclonic epilepsy 8 (EJM8) [MIM:607628]: A subtype
CC of idiopathic generalized epilepsy. Patients have afebrile seizures
CC only, with onset in adolescence (rather than in childhood) and
CC myoclonic jerks which usually occur after awakening and are triggered
CC by sleep deprivation and fatigue. {ECO:0000269|PubMed:19191339}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- DISEASE: Leukoencephalopathy with ataxia (LKPAT) [MIM:615651]: An
CC autosomal recessive neurologic disorder with a characteristic pattern
CC of white matter abnormalities on brain MRI. Affected individuals have
CC prominent signal abnormalities and decreased apparent diffusion
CC coefficient values in the posterior limbs of the internal capsules,
CC middle cerebral peduncles, pyramidal tracts in the pons, and middle
CC cerebellar peduncles, suggesting myelin microvacuolation. Clinical
CC features include ataxia and unstable gait. More variable abnormalities
CC may include visual field defects, headaches, and learning disabilities.
CC {ECO:0000269|PubMed:23707145}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hyperaldosteronism, familial, 2 (HALD2) [MIM:605635]: An
CC autosomal dominant disorder characterized by elevated plasma
CC aldosterone level and hypertension of varying severity even within
CC members of the same family. Hypokalemia is observed in some patients.
CC In HALD2, hypertension does not improve with glucocorticoid treatment.
CC {ECO:0000269|PubMed:29403011, ECO:0000269|PubMed:29403012}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: The CLC channel family contains both chloride channels
CC and proton-coupled anion transporters that exchange chloride or another
CC anion for protons. The absence of conserved gating glutamate residues
CC is typical for family members that function as channels (By
CC similarity). {ECO:0000250}.
CC -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-
CC 2/CLCN2 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH21578.1; Type=Erroneous translation; Note=Wrong choice of frame.; Evidence={ECO:0000305};
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DR EMBL; S77770; AAB34722.2; -; mRNA.
DR EMBL; AF026004; AAB88807.1; -; mRNA.
DR EMBL; AK298952; BAG61051.1; -; mRNA.
DR EMBL; AK302759; BAG63970.1; -; mRNA.
DR EMBL; AC078797; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC021578; AAH21578.1; ALT_SEQ; mRNA.
DR EMBL; BC072004; AAH72004.1; -; mRNA.
DR CCDS; CCDS3263.1; -. [P51788-1]
DR CCDS; CCDS54690.1; -. [P51788-4]
DR CCDS; CCDS54691.1; -. [P51788-3]
DR CCDS; CCDS54692.1; -. [P51788-5]
DR RefSeq; NP_001164558.1; NM_001171087.2. [P51788-3]
DR RefSeq; NP_001164559.1; NM_001171088.2. [P51788-4]
DR RefSeq; NP_001164560.1; NM_001171089.2. [P51788-5]
DR RefSeq; NP_004357.3; NM_004366.5. [P51788-1]
DR AlphaFoldDB; P51788; -.
DR SMR; P51788; -.
DR BioGRID; 107595; 50.
DR IntAct; P51788; 33.
DR STRING; 9606.ENSP00000265593; -.
DR ChEMBL; CHEMBL1628478; -.
DR DrugBank; DB05514; Cobiprostone.
DR DrugBank; DB01046; Lubiprostone.
DR DrugCentral; P51788; -.
DR GuidetoPHARMACOLOGY; 699; -.
DR TCDB; 2.A.49.2.12; the chloride carrier/channel (clc) family.
DR GlyGen; P51788; 1 site.
DR iPTMnet; P51788; -.
DR PhosphoSitePlus; P51788; -.
DR BioMuta; CLCN2; -.
DR DMDM; 288558807; -.
DR EPD; P51788; -.
DR jPOST; P51788; -.
DR MassIVE; P51788; -.
DR MaxQB; P51788; -.
DR PaxDb; P51788; -.
DR PeptideAtlas; P51788; -.
DR PRIDE; P51788; -.
DR ProteomicsDB; 19203; -.
DR ProteomicsDB; 19425; -.
DR ProteomicsDB; 56385; -. [P51788-1]
DR ProteomicsDB; 56387; -. [P51788-3]
DR Antibodypedia; 2994; 311 antibodies from 36 providers.
DR DNASU; 1181; -.
DR Ensembl; ENST00000265593.9; ENSP00000265593.4; ENSG00000114859.16. [P51788-1]
DR Ensembl; ENST00000344937.11; ENSP00000345056.7; ENSG00000114859.16. [P51788-3]
DR Ensembl; ENST00000434054.6; ENSP00000400425.2; ENSG00000114859.16. [P51788-4]
DR Ensembl; ENST00000457512.1; ENSP00000391928.1; ENSG00000114859.16. [P51788-5]
DR GeneID; 1181; -.
DR KEGG; hsa:1181; -.
DR MANE-Select; ENST00000265593.9; ENSP00000265593.4; NM_004366.6; NP_004357.3.
DR UCSC; uc003foi.4; human. [P51788-1]
DR CTD; 1181; -.
DR DisGeNET; 1181; -.
DR GeneCards; CLCN2; -.
DR GeneReviews; CLCN2; -.
DR HGNC; HGNC:2020; CLCN2.
DR HPA; ENSG00000114859; Tissue enhanced (intestine).
DR MalaCards; CLCN2; -.
DR MIM; 600570; gene.
DR MIM; 605635; phenotype.
DR MIM; 607628; phenotype.
DR MIM; 615651; phenotype.
DR neXtProt; NX_P51788; -.
DR OpenTargets; ENSG00000114859; -.
DR Orphanet; 404; Familial hyperaldosteronism type II.
DR Orphanet; 307; Juvenile myoclonic epilepsy.
DR Orphanet; 363540; Leukoencephalopathy with mild cerebellar ataxia and white matter edema.
DR PharmGKB; PA26547; -.
DR VEuPathDB; HostDB:ENSG00000114859; -.
DR eggNOG; KOG0476; Eukaryota.
DR GeneTree; ENSGT00940000155439; -.
DR HOGENOM; CLU_006904_0_1_1; -.
DR InParanoid; P51788; -.
DR OMA; ACFMFNN; -.
DR OrthoDB; 1131873at2759; -.
DR PhylomeDB; P51788; -.
DR TreeFam; TF300522; -.
DR PathwayCommons; P51788; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; P51788; -.
DR BioGRID-ORCS; 1181; 8 hits in 1076 CRISPR screens.
DR ChiTaRS; CLCN2; human.
DR GeneWiki; CLCN2; -.
DR GenomeRNAi; 1181; -.
DR Pharos; P51788; Tclin.
DR PRO; PR:P51788; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P51788; protein.
DR Bgee; ENSG00000114859; Expressed in mucosa of transverse colon and 106 other tissues.
DR ExpressionAtlas; P51788; baseline and differential.
DR Genevisible; P51788; HS.
DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005247; F:voltage-gated chloride channel activity; IDA:UniProtKB.
DR GO; GO:0090425; P:acinar cell differentiation; IEA:Ensembl.
DR GO; GO:0060689; P:cell differentiation involved in salivary gland development; IEA:Ensembl.
DR GO; GO:0006821; P:chloride transport; IBA:GO_Central.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0032347; P:regulation of aldosterone biosynthetic process; IMP:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR Gene3D; 3.10.580.10; -; 2.
DR InterPro; IPR046342; CBS_dom_sf.
DR InterPro; IPR002244; Cl-channel-2.
DR InterPro; IPR014743; Cl-channel_core.
DR InterPro; IPR001807; Cl-channel_volt-gated.
DR Pfam; PF00654; Voltage_CLC; 1.
DR PRINTS; PR00762; CLCHANNEL.
DR PRINTS; PR01113; CLCHANNEL2.
DR SUPFAM; SSF54631; SSF54631; 1.
DR SUPFAM; SSF81340; SSF81340; 1.
DR PROSITE; PS51371; CBS; 2.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; CBS domain; Cell membrane; Chloride;
KW Chloride channel; Disease variant; Epilepsy; Ion channel; Ion transport;
KW Membrane; Phosphoprotein; Reference proteome; Repeat; Transmembrane;
KW Transmembrane helix; Transport; Voltage-gated channel.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22814378"
FT CHAIN 2..898
FT /note="Chloride channel protein 2"
FT /id="PRO_0000094433"
FT TOPO_DOM 2..87
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 88..121
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 130..155
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 164..171
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 180..198
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 205..223
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 239..251
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 255..263
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 275..295
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 321..349
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 358..377
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 429..449
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 457..480
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 497..511
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 512..513
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT INTRAMEM 514..525
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 526..530
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT TRANSMEM 531..548
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TOPO_DOM 549..898
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT DOMAIN 584..642
FT /note="CBS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT DOMAIN 790..850
FT /note="CBS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT REGION 643..672
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 686..717
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 856..898
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 161..165
FT /note="Selectivity filter part_1"
FT /evidence="ECO:0000250"
FT MOTIF 203..207
FT /note="Selectivity filter part_2"
FT /evidence="ECO:0000250"
FT MOTIF 457..461
FT /note="Selectivity filter part_3"
FT /evidence="ECO:0000250"
FT COMPBIAS 857..871
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 162
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 459
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 553
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 20
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9R0A1"
FT MOD_RES 712
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 758
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35525"
FT VAR_SEQ 1..359
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_007831"
FT VAR_SEQ 74..117
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045457"
FT VAR_SEQ 443..485
FT /note="FWMSALATTIPVPCGAFMPVFVIGAAFGRLVGESMAAWFPDGI -> HLGVW
FT WVKAWLPGSQMEFIRTAAPTGLCLGATLWSGQLRWQER (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_007832"
FT VAR_SEQ 466..482
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_036456"
FT VAR_SEQ 486..898
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_036455"
FT VAR_SEQ 806..834
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045458"
FT VARIANT 22
FT /note="M -> K (in HALD2; increased voltage-gated chloride
FT currents due to higher channel open probabilities at
FT physiological cell membrane potentials; dbSNP:rs758379595)"
FT /evidence="ECO:0000269|PubMed:29403011"
FT /id="VAR_081154"
FT VARIANT 24
FT /note="G -> D (in HALD2; increased voltage-gated chloride
FT currents; increased aldosterone synthase expression;
FT dbSNP:rs1085307938)"
FT /evidence="ECO:0000269|PubMed:29403012"
FT /id="VAR_081155"
FT VARIANT 26
FT /note="Y -> N (in HALD2; increased voltage-gated chloride
FT currents due to higher channel open probabilitiesat at
FT physiological cell membrane potentials;
FT dbSNP:rs1553857113)"
FT /evidence="ECO:0000269|PubMed:29403011"
FT /id="VAR_081156"
FT VARIANT 48
FT /note="P -> R (reduces channel activity;
FT dbSNP:rs115661422)"
FT /evidence="ECO:0000269|PubMed:17762171"
FT /id="VAR_057886"
FT VARIANT 68
FT /note="R -> H (reduces channel activity; dbSNP:rs61729156)"
FT /evidence="ECO:0000269|PubMed:17762171"
FT /id="VAR_057887"
FT VARIANT 144..145
FT /note="Missing (in LKPAT; loss of function mutation; the
FT mutant protein is restricted to the endoplasmic reticulum
FT and hardly reached the plasma membrane; lower amounts of
FT the mutant protein compared to wild-type)"
FT /evidence="ECO:0000269|PubMed:23707145"
FT /id="VAR_070976"
FT VARIANT 172
FT /note="R -> Q (in HALD2; increased voltage-gated chloride
FT currents due to higher channel open probabilities at
FT physiological cell membrane potentials; increased
FT aldosterone synthase expression; dbSNP:rs1293789661)"
FT /evidence="ECO:0000269|PubMed:29403011"
FT /id="VAR_081157"
FT VARIANT 199
FT /note="G -> A (no effect; dbSNP:rs863225248)"
FT /evidence="ECO:0000269|PubMed:17762171"
FT /id="VAR_057888"
FT VARIANT 235
FT /note="R -> Q (in EJM8; associated with disease
FT susceptibility; the mutant channel has accelerated
FT deactivation rates compared to wild-type, but normal
FT activation and peak current; dbSNP:rs71318369)"
FT /evidence="ECO:0000269|PubMed:19191339"
FT /id="VAR_057889"
FT VARIANT 362
FT /note="Missing (in HALD2; increased voltage-gated chloride
FT currents due to higher channel open probabilities at
FT physiological cell membrane potentials)"
FT /evidence="ECO:0000269|PubMed:29403011"
FT /id="VAR_081158"
FT VARIANT 500
FT /note="A -> V (in LKPAT; loss of function mutation; the
FT mutant protein is restricted to the endoplasmic reticulum
FT and hardly reaches the plasma membrane; lower amounts of
FT the mutant protein compared to wild-type;
FT dbSNP:rs587777111)"
FT /evidence="ECO:0000269|PubMed:23707145"
FT /id="VAR_070977"
FT VARIANT 577
FT /note="R -> Q (in EIG11; associated with disease
FT susceptibility; the mutant channel has accelerated
FT deactivation rates compared to wild-type, but normal
FT activation and peak current; dbSNP:rs137852682)"
FT /evidence="ECO:0000269|PubMed:19191339"
FT /id="VAR_057890"
FT VARIANT 644
FT /note="R -> C (no effect; dbSNP:rs148545588)"
FT /evidence="ECO:0000269|PubMed:19191339"
FT /id="VAR_057891"
FT VARIANT 646
FT /note="R -> Q (reduces channel activity;
FT dbSNP:rs115961753)"
FT /evidence="ECO:0000269|PubMed:17762171"
FT /id="VAR_057892"
FT VARIANT 668
FT /note="T -> S (in dbSNP:rs9820367)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:17762171, ECO:0000269|PubMed:7795595"
FT /id="VAR_054550"
FT VARIANT 715
FT /note="G -> E (in JAE2; unknown pathological significance;
FT dbSNP:rs137852681)"
FT /evidence="ECO:0000269|PubMed:19710712"
FT /id="VAR_015989"
FT VARIANT 718
FT /note="E -> D (in dbSNP:rs2228292)"
FT /id="VAR_054551"
FT VARIANT 719
FT /note="S -> L (found in a patient with childhood absence
FT epilepsy; unknown pathological significance;
FT dbSNP:rs138573287)"
FT /evidence="ECO:0000269|PubMed:19200853"
FT /id="VAR_058426"
FT VARIANT 725
FT /note="R -> W (slightly faster channel activation;
FT dbSNP:rs114702742)"
FT /evidence="ECO:0000269|PubMed:17762171"
FT /id="VAR_057893"
FT VARIANT 747
FT /note="R -> H (slightly faster channel activation;
FT dbSNP:rs144164281)"
FT /evidence="ECO:0000269|PubMed:17762171"
FT /id="VAR_057894"
FT VARIANT 865
FT /note="S -> R (in HALD2; increased voltage-gated chloride
FT currents due to higher channel open probabilities at
FT physiological cell membrane potentials;
FT dbSNP:rs1553853557)"
FT /evidence="ECO:0000269|PubMed:29403011"
FT /id="VAR_081159"
FT CONFLICT 17
FT /note="Y -> H (in Ref. 1; AAB34722)"
FT /evidence="ECO:0000305"
FT CONFLICT 537
FT /note="A -> V (in Ref. 5; AAH21578)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 898 AA; 98535 MW; 5F20FA8713C0C74E CRC64;
MAAAAAEEGM EPRALQYEQT LMYGRYTQDL GAFAKEEAAR IRLGGPEPWK GPPSSRAAPE
LLEYGRSRCA RCRVCSVRCH KFLVSRVGED WIFLVLLGLL MALVSWVMDY AIAACLQAQQ
WMSRGLNTSI LLQYLAWVTY PVVLITFSAG FTQILAPQAV GSGIPEMKTI LRGVVLKEYL
TLKTFIAKVI GLTCALGSGM PLGKEGPFVH IASMCAALLS KFLSLFGGIY ENESRNTEML
AAACAVGVGC CFAAPIGGVL FSIEVTSTFF AVRNYWRGFF AATFSAFIFR VLAVWNRDEE
TITALFKTRF RLDFPFDLQE LPAFAVIGIA SGFGGALFVY LNRKIVQVMR KQKTINRFLM
RKRLLFPALV TLLISTLTFP PGFGQFMAGQ LSQKETLVTL FDNRTWVRQG LVEELEPPST
SQAWNPPRAN VFLTLVIFIL MKFWMSALAT TIPVPCGAFM PVFVIGAAFG RLVGESMAAW
FPDGIHTDSS TYRIVPGGYA VVGAAALAGA VTHTVSTAVI VFELTGQIAH ILPVMIAVIL
ANAVAQSLQP SLYDSIIRIK KLPYLPELGW GRHQQYRVRV EDIMVRDVPH VALSCTFRDL
RLALHRTKGR MLALVESPES MILLGSIERS QVVALLGAQL SPARRRQHMQ ERRATQTSPL
SDQEGPPTPE ASVCFQVNTE DSAFPAARGE THKPLKPALK RGPSVTRNLG ESPTGSAESA
GIALRSLFCG SPPPEAASEK LESCEKRKLK RVRISLASDA DLEGEMSPEE ILEWEEQQLD
EPVNFSDCKI DPAPFQLVER TSLHKTHTIF SLLGVDHAYV TSIGRLIGIV TLKELRKAIE
GSVTAQGVKV RPPLASFRDS ATSSSDTETT EVHALWGPHS RHGLPREGSP SDSDDKCQ
