CLCN4_HUMAN
ID CLCN4_HUMAN Reviewed; 760 AA.
AC P51793; A1L3U1; B7Z5Z4; Q9UBU1;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 11-FEB-2002, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=H(+)/Cl(-) exchange transporter 4;
DE AltName: Full=Chloride channel protein 4;
DE Short=ClC-4;
DE AltName: Full=Chloride transporter ClC-4;
GN Name=CLCN4;
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).
RC TISSUE=Retina;
RX PubMed=8069296; DOI=10.1093/hmg/3.4.547;
RA van Slegtenhorst M.A., Bassi M.T., Borsani G., Wapenaar M.C., Ferrero G.B.,
RA de Conciliis L., Rugarli E.I., Grillo A., Franco B., Zoghbi H.Y.,
RA Ballabio A.;
RT "A gene from the Xp22.3 region shares homology with voltage-gated chloride
RT channels.";
RL Hum. Mol. Genet. 3:547-552(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Skeletal muscle;
RX PubMed=10564087; DOI=10.1152/ajpcell.1999.277.5.c948;
RA Kawasaki M., Fukuma T., Yamauchi K., Sakamoto H., Marumo F., Sasaki S.;
RT "Identification of an acid-activated Cl- channel from human skeletal
RT muscles.";
RL Am. J. Physiol. 277:C948-C954(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lens epithelium;
RA Rae J.L.;
RT "A chloride channel (ClC-4) in human lens epithelium.";
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Cerebellum;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [8]
RP SUBCELLULAR LOCATION.
RX PubMed=17023393; DOI=10.1096/fj.05-5588fje;
RA Okkenhaug H., Weylandt K.H., Carmena D., Wells D.J., Higgins C.F.,
RA Sardini A.;
RT "The human ClC-4 protein, a member of the CLC chloride channel/transporter
RT family, is localized to the endoplasmic reticulum by its N-terminus.";
RL FASEB J. 20:2390-2392(2006).
RN [9]
RP FUNCTION, AND MUTAGENESIS OF GLU-224 AND GLU-281.
RX PubMed=18063579; DOI=10.1074/jbc.m708368200;
RA Zdebik A.A., Zifarelli G., Bergsdorf E.-Y., Soliani P., Scheel O.,
RA Jentsch T.J., Pusch M.;
RT "Determinants of anion-proton coupling in mammalian endosomal CLC
RT proteins.";
RL J. Biol. Chem. 283:4219-4227(2008).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=28972156; DOI=10.1074/jbc.m117.801951;
RA Guzman R.E., Bungert-Pluemke S., Franzen A., Fahlke C.;
RT "Preferential association with ClC-3 permits sorting of ClC-4 into
RT endosomal compartments.";
RL J. Biol. Chem. 292:19055-19065(2017).
RN [11]
RP REVIEW.
RX PubMed=29845874; DOI=10.1152/physrev.00047.2017;
RA Jentsch T.J., Pusch M.;
RT "CLC Chloride Channels and Transporters: Structure, Function, Physiology,
RT and Disease.";
RL Physiol. Rev. 98:1493-1590(2018).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN MRXSRC, VARIANT MRXSRC
RP ARG-544, AND CHARACTERIZATION OF VARIANT MRXSRC ARG-544.
RX PubMed=23647072; DOI=10.1111/epi.12201;
RA Veeramah K.R., Johnstone L., Karafet T.M., Wolf D., Sprissler R.,
RA Salogiannis J., Barth-Maron A., Greenberg M.E., Stuhlmann T., Weinert S.,
RA Jentsch T.J., Pazzi M., Restifo L.L., Talwar D., Erickson R.P.,
RA Hammer M.F.;
RT "Exome sequencing reveals new causal mutations in children with epileptic
RT encephalopathies.";
RL Epilepsia 54:1270-1281(2013).
RN [13]
RP VARIANT ASN-15.
RX PubMed=26034137; DOI=10.1093/hmg/ddv196;
RA Yu L., Sawle A.D., Wynn J., Aspelund G., Stolar C.J., Arkovitz M.S.,
RA Potoka D., Azarow K.S., Mychaliska G.B., Shen Y., Chung W.K.;
RT "Increased burden of de novo predicted deleterious variants in complex
RT congenital diaphragmatic hernia.";
RL Hum. Mol. Genet. 24:4764-4773(2015).
RN [14]
RP VARIANTS MRXSRC ASN-15; SER-78; GLY-212; PRO-221; VAL-221; MET-275;
RP LEU-534; MET-536; ARG-544; VAL-555; TRP-718 AND ARG-731, CHARACTERIZATION
RP OF VARIANTS MRXSRC ASN-15; GLY-212; PRO-221; MET-275; LEU-534; VAL-555 AND
RP TRP-718, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=27550844; DOI=10.1038/mp.2016.135;
RG DDD Study;
RA Palmer E.E., Stuhlmann T., Weinert S., Haan E., Van Esch H., Holvoet M.,
RA Boyle J., Leffler M., Raynaud M., Moraine C., van Bokhoven H.,
RA Kleefstra T., Kahrizi K., Najmabadi H., Ropers H.H., Delgado M.R.,
RA Sirsi D., Golla S., Sommer A., Pietryga M.P., Chung W.K., Wynn J.,
RA Rohena L., Bernardo E., Hamlin D., Faux B.M., Grange D.K., Manwaring L.,
RA Tolmie J., Joss S., Cobben J.M., Duijkers F.A.M., Goehringer J.M.,
RA Challman T.D., Hennig F., Fischer U., Grimme A., Suckow V., Musante L.,
RA Nicholl J., Shaw M., Lodh S.P., Niu Z., Rosenfeld J.A., Stankiewicz P.,
RA Jentsch T.J., Gecz J., Field M., Kalscheuer V.M.;
RT "De novo and inherited mutations in the X-linked gene CLCN4 are associated
RT with syndromic intellectual disability and behavior and seizure disorders
RT in males and females.";
RL Mol. Psychiatry 23:222-230(2018).
RN [15]
RP FUNCTION, INVOLVEMENT IN MRXSRC, VARIANTS MRXSRC SER-78; VAL-221; MET-536
RP AND ARG-731, AND CHARACTERIZATION OF VARIANTS MRXSRC SER-78; VAL-221;
RP MET-536 AND ARG-731.
RX PubMed=25644381; DOI=10.1038/mp.2014.193;
RA Hu H., Haas S.A., Chelly J., Van Esch H., Raynaud M., de Brouwer A.P.,
RA Weinert S., Froyen G., Frints S.G., Laumonnier F., Zemojtel T., Love M.I.,
RA Richard H., Emde A.K., Bienek M., Jensen C., Hambrock M., Fischer U.,
RA Langnick C., Feldkamp M., Wissink-Lindhout W., Lebrun N., Castelnau L.,
RA Rucci J., Montjean R., Dorseuil O., Billuart P., Stuhlmann T., Shaw M.,
RA Corbett M.A., Gardner A., Willis-Owen S., Tan C., Friend K.L., Belet S.,
RA van Roozendaal K.E., Jimenez-Pocquet M., Moizard M.P., Ronce N., Sun R.,
RA O'Keeffe S., Chenna R., van Boemmel A., Goeke J., Hackett A., Field M.,
RA Christie L., Boyle J., Haan E., Nelson J., Turner G., Baynam G.,
RA Gillessen-Kaesbach G., Mueller U., Steinberger D., Budny B.,
RA Badura-Stronka M., Latos-Bielenska A., Ousager L.B., Wieacker P.,
RA Rodriguez Criado G., Bondeson M.L., Anneren G., Dufke A., Cohen M.,
RA Van Maldergem L., Vincent-Delorme C., Echenne B., Simon-Bouy B.,
RA Kleefstra T., Willemsen M., Fryns J.P., Devriendt K., Ullmann R.,
RA Vingron M., Wrogemann K., Wienker T.F., Tzschach A., van Bokhoven H.,
RA Gecz J., Jentsch T.J., Chen W., Ropers H.H., Kalscheuer V.M.;
RT "X-exome sequencing of 405 unresolved families identifies seven novel
RT intellectual disability genes.";
RL Mol. Psychiatry 21:133-148(2016).
CC -!- FUNCTION: Strongly outwardly rectifying, electrogenic
CC H(+)/Cl(-)exchanger which mediates the exchange of chloride ions
CC against protons (PubMed:18063579, PubMed:28972156, PubMed:23647072,
CC PubMed:27550844, PubMed:25644381). The CLC channel family contains both
CC chloride channels and proton-coupled anion transporters that exchange
CC chloride or another anion for protons (PubMed:29845874). The presence
CC of conserved gating glutamate residues is typical for family members
CC that function as antiporters (PubMed:29845874).
CC {ECO:0000269|PubMed:18063579, ECO:0000269|PubMed:23647072,
CC ECO:0000269|PubMed:25644381, ECO:0000269|PubMed:27550844,
CC ECO:0000269|PubMed:28972156, ECO:0000303|PubMed:29845874}.
CC -!- SUBUNIT: Monomer (PubMed:28972156). Forms heterodimers with CLCN3
CC (PubMed:28972156). {ECO:0000269|PubMed:28972156}.
CC -!- INTERACTION:
CC P51793; Q8WTS1: ABHD5; NbExp=3; IntAct=EBI-22754239, EBI-2813554;
CC -!- SUBCELLULAR LOCATION: Early endosome membrane
CC {ECO:0000250|UniProtKB:P51794}; Multi-pass membrane protein
CC {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:28972156};
CC Multi-pass membrane protein {ECO:0000255}. Endoplasmic reticulum
CC membrane {ECO:0000269|PubMed:17023393, ECO:0000269|PubMed:28972156};
CC Multi-pass membrane protein {ECO:0000255}. Lysosome membrane
CC {ECO:0000269|PubMed:28972156}; Multi-pass membrane protein
CC {ECO:0000255}. Recycling endosome membrane
CC {ECO:0000269|PubMed:28972156}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Localizes to late endosome membrane, lysosome
CC membrane and recycling endosome membrane in the presence of CLCN3.
CC {ECO:0000269|PubMed:28972156}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P51793-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P51793-2; Sequence=VSP_054658;
CC -!- TISSUE SPECIFICITY: Abundant in skeletal muscle and also detectable in
CC brain and heart.
CC -!- DISEASE: Raynaud-Claes syndrome (MRXSRC) [MIM:300114]: An X-linked
CC syndrome characterized by borderline to severe intellectual disability
CC and impaired language development. Additional features include
CC behavioral problems, psychiatric disorders, seizures, progressive
CC ataxia, brain abnormalities, and facial dysmorphisms.
CC {ECO:0000269|PubMed:23647072, ECO:0000269|PubMed:25644381,
CC ECO:0000269|PubMed:27550844}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-
CC 4/CLCN4 subfamily. {ECO:0000305}.
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DR EMBL; X77197; CAA54417.1; -; mRNA.
DR EMBL; AB019432; BAA77327.1; -; mRNA.
DR EMBL; AF170492; AAD50981.1; -; mRNA.
DR EMBL; AK289564; BAF82253.1; -; mRNA.
DR EMBL; AK299611; BAH13080.1; -; mRNA.
DR EMBL; AC003666; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC121345; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471074; EAW98778.1; -; Genomic_DNA.
DR EMBL; BC130278; AAI30279.1; -; mRNA.
DR CCDS; CCDS14137.1; -. [P51793-1]
DR CCDS; CCDS59159.1; -. [P51793-2]
DR PIR; I37242; I37242.
DR RefSeq; NP_001243873.1; NM_001256944.1. [P51793-2]
DR RefSeq; NP_001821.2; NM_001830.3. [P51793-1]
DR AlphaFoldDB; P51793; -.
DR SMR; P51793; -.
DR BioGRID; 107597; 3.
DR IntAct; P51793; 1.
DR STRING; 9606.ENSP00000370213; -.
DR GuidetoPHARMACOLOGY; 703; -.
DR TCDB; 2.A.49.2.8; the chloride carrier/channel (clc) family.
DR iPTMnet; P51793; -.
DR PhosphoSitePlus; P51793; -.
DR BioMuta; CLCN4; -.
DR DMDM; 20141247; -.
DR jPOST; P51793; -.
DR MassIVE; P51793; -.
DR MaxQB; P51793; -.
DR PaxDb; P51793; -.
DR PeptideAtlas; P51793; -.
DR PRIDE; P51793; -.
DR ProteomicsDB; 56390; -. [P51793-1]
DR ProteomicsDB; 6731; -.
DR ABCD; P51793; 1 sequenced antibody.
DR Antibodypedia; 23690; 180 antibodies from 30 providers.
DR DNASU; 1183; -.
DR Ensembl; ENST00000380833.9; ENSP00000370213.4; ENSG00000073464.13. [P51793-1]
DR Ensembl; ENST00000674669.1; ENSP00000501922.1; ENSG00000073464.13. [P51793-2]
DR GeneID; 1183; -.
DR KEGG; hsa:1183; -.
DR MANE-Select; ENST00000380833.9; ENSP00000370213.4; NM_001830.4; NP_001821.2.
DR UCSC; uc004csy.5; human. [P51793-1]
DR CTD; 1183; -.
DR DisGeNET; 1183; -.
DR GeneCards; CLCN4; -.
DR GeneReviews; CLCN4; -.
DR HGNC; HGNC:2022; CLCN4.
DR HPA; ENSG00000073464; Tissue enhanced (brain, retina, skeletal muscle, tongue).
DR MalaCards; CLCN4; -.
DR MIM; 300114; phenotype.
DR MIM; 302910; gene.
DR neXtProt; NX_P51793; -.
DR OpenTargets; ENSG00000073464; -.
DR Orphanet; 485350; CLCN4-related X-linked intellectual disability syndrome.
DR Orphanet; 777; X-linked non-syndromic intellectual disability.
DR PharmGKB; PA26549; -.
DR VEuPathDB; HostDB:ENSG00000073464; -.
DR eggNOG; KOG0475; Eukaryota.
DR GeneTree; ENSGT00940000158265; -.
DR HOGENOM; CLU_003181_2_1_1; -.
DR InParanoid; P51793; -.
DR OMA; KYAGLVH; -.
DR OrthoDB; 271925at2759; -.
DR PhylomeDB; P51793; -.
DR TreeFam; TF313867; -.
DR PathwayCommons; P51793; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; P51793; -.
DR SIGNOR; P51793; -.
DR BioGRID-ORCS; 1183; 6 hits in 695 CRISPR screens.
DR ChiTaRS; CLCN4; human.
DR GeneWiki; CLCN4; -.
DR GenomeRNAi; 1183; -.
DR Pharos; P51793; Tchem.
DR PRO; PR:P51793; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; P51793; protein.
DR Bgee; ENSG00000073464; Expressed in middle temporal gyrus and 168 other tissues.
DR ExpressionAtlas; P51793; baseline and differential.
DR Genevisible; P51793; HS.
DR GO; GO:0097546; C:ciliary base; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; IBA:GO_Central.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008021; C:synaptic vesicle; IBA:GO_Central.
DR GO; GO:0015297; F:antiporter activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005254; F:chloride channel activity; IDA:MGI.
DR GO; GO:0015299; F:solute:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0005247; F:voltage-gated chloride channel activity; IBA:GO_Central.
DR GO; GO:0006821; P:chloride transport; IDA:MGI.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:1905515; P:non-motile cilium assembly; IEA:Ensembl.
DR InterPro; IPR000644; CBS_dom.
DR InterPro; IPR046342; CBS_dom_sf.
DR InterPro; IPR014743; Cl-channel_core.
DR InterPro; IPR001807; Cl-channel_volt-gated.
DR InterPro; IPR002246; Cl_channel-4.
DR PANTHER; PTHR45711:SF2; PTHR45711:SF2; 1.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00654; Voltage_CLC; 1.
DR PRINTS; PR00762; CLCHANNEL.
DR PRINTS; PR01115; CLCHANNEL4.
DR SMART; SM00116; CBS; 2.
DR SUPFAM; SSF54631; SSF54631; 1.
DR SUPFAM; SSF81340; SSF81340; 1.
DR PROSITE; PS51371; CBS; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Antiport; ATP-binding; CBS domain; Chloride;
KW Disease variant; Endoplasmic reticulum; Endosome; Intellectual disability;
KW Ion transport; Lysosome; Membrane; Nucleotide-binding; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..760
FT /note="H(+)/Cl(-) exchange transporter 4"
FT /id="PRO_0000094443"
FT TOPO_DOM 1..67
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 68..105
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 151..174
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 183..190
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 200..218
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 224..243
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 255..267
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 271..279
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 291..309
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 333..358
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 365..385
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 442..462
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 467..486
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 514..528
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 532..543
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 544..547
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 548..566
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TOPO_DOM 567..760
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT DOMAIN 600..666
FT /note="CBS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT DOMAIN 697..755
FT /note="CBS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT REGION 14..63
FT /note="Required for localization in the endoplasmic
FT reticulum"
FT /evidence="ECO:0000269|PubMed:17023393"
FT REGION 667..696
FT /note="Required for localization in the endoplasmic
FT reticulum"
FT /evidence="ECO:0000269|PubMed:28972156"
FT MOTIF 180..184
FT /note="Selectivity filter part_1"
FT /evidence="ECO:0000250"
FT MOTIF 222..226
FT /note="Selectivity filter part_2"
FT /evidence="ECO:0000250"
FT MOTIF 467..471
FT /note="Selectivity filter part_3"
FT /evidence="ECO:0000250"
FT BINDING 181
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 469
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 572
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 610
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 631..633
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P51795"
FT BINDING 738..741
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P51795"
FT SITE 224
FT /note="Mediates proton transfer from the outer aqueous
FT phase to the interior of the protein; involved in linking
FT H(+) and Cl(-) transport"
FT SITE 281
FT /note="Mediates proton transfer from the protein to the
FT inner aqueous phase"
FT VAR_SEQ 1..94
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054658"
FT VARIANT 15
FT /note="D -> N (in MRXSRC; also in patients with complex
FT congenital diaphragmatic hernia; unknown pathological
FT significance; no reduction in outwardly-rectifying
FT currents; does not affect its localization in endoplasmic
FT reticulum membrane; dbSNP:rs879255591)"
FT /evidence="ECO:0000269|PubMed:26034137,
FT ECO:0000269|PubMed:27550844"
FT /id="VAR_083577"
FT VARIANT 78
FT /note="G -> S (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; dbSNP:rs1569226551)"
FT /evidence="ECO:0000269|PubMed:25644381,
FT ECO:0000269|PubMed:27550844"
FT /id="VAR_077819"
FT VARIANT 212
FT /note="V -> G (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; does not affect its localization in
FT endoplasmic reticulum membrane; dbSNP:rs879255580)"
FT /evidence="ECO:0000269|PubMed:27550844"
FT /id="VAR_083578"
FT VARIANT 221
FT /note="L -> P (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; does not affect its localization in
FT endoplasmic reticulum membrane; dbSNP:rs879255581)"
FT /evidence="ECO:0000269|PubMed:27550844"
FT /id="VAR_083579"
FT VARIANT 221
FT /note="L -> V (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; dbSNP:rs1569230006)"
FT /evidence="ECO:0000269|PubMed:25644381,
FT ECO:0000269|PubMed:27550844"
FT /id="VAR_077820"
FT VARIANT 275
FT /note="V -> M (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; does not affect its localization in
FT endoplasmic reticulum; dbSNP:rs879255585)"
FT /evidence="ECO:0000269|PubMed:27550844"
FT /id="VAR_083580"
FT VARIANT 534
FT /note="S -> L (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; does not affect its localization in
FT endoplasmic reticulum membrane; dbSNP:rs879255582)"
FT /evidence="ECO:0000269|PubMed:27550844"
FT /id="VAR_083581"
FT VARIANT 536
FT /note="V -> M (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; dbSNP:rs1569231897)"
FT /evidence="ECO:0000269|PubMed:25644381,
FT ECO:0000269|PubMed:27550844"
FT /id="VAR_077821"
FT VARIANT 544
FT /note="G -> R (in MRXSRC; has normal localization to
FT structures resembling endoplasmic reticulum membranes;
FT almost abolishes the outwardly-rectifying currents;
FT dbSNP:rs587777161)"
FT /evidence="ECO:0000269|PubMed:23647072,
FT ECO:0000269|PubMed:27550844"
FT /id="VAR_077822"
FT VARIANT 555
FT /note="A -> V (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; does not affect its localization in
FT endoplasmic reticulum membrane; dbSNP:rs879255583)"
FT /evidence="ECO:0000269|PubMed:27550844"
FT /id="VAR_083582"
FT VARIANT 718
FT /note="R -> W (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; does not affect its localization in
FT endoplasmic reticulum membrane; dbSNP:rs879255584)"
FT /evidence="ECO:0000269|PubMed:27550844"
FT /id="VAR_083583"
FT VARIANT 731
FT /note="G -> R (in MRXSRC; marked reduction in outwardly-
FT rectifying currents; dbSNP:rs1569233549)"
FT /evidence="ECO:0000269|PubMed:25644381,
FT ECO:0000269|PubMed:27550844"
FT /id="VAR_077823"
FT MUTAGEN 224
FT /note="E->A: Restores chloride translocation, but not
FT proton transport; when associated with A-281."
FT /evidence="ECO:0000269|PubMed:18063579"
FT MUTAGEN 281
FT /note="E->A: Abolishes translocation of protons and
FT chloride ions."
FT /evidence="ECO:0000269|PubMed:18063579"
FT CONFLICT 178
FT /note="A -> R (in Ref. 1; CAA54417)"
FT /evidence="ECO:0000305"
FT CONFLICT 498..499
FT /note="II -> YY (in Ref. 1; CAA54417)"
FT /evidence="ECO:0000305"
FT CONFLICT 659
FT /note="K -> N (in Ref. 1; CAA54417)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 760 AA; 84917 MW; 3A5A25D1FEF3F217 CRC64;
MVNAGAMSGS GNLMDFLDEP FPDVGTYEDF HTIDWLREKS RDTDRHRKIT SKSKESIWEF
IKSLLDAWSG WVVMLLIGLL AGTLAGVIDL AVDWMTDLKE GVCLSAFWYS HEQCCWTSNE
TTFEDRDKCP LWQKWSELLV NQSEGASAYI LNYLMYILWA LLFAFLAVSL VRVFAPYACG
SGIPEIKTIL SGFIIRGYLG KWTLLIKTVT LVLVVSSGLS LGKEGPLVHV ACCCGNFFSS
LFSKYSKNEG KRREVLSAAA AAGVSVAFGA PIGGVLFSLE EVSYYFPLKT LWRSFFAALV
AAFTLRSINP FGNSRLVLFY VEYHTPWYMA ELFPFILLGV FGGLWGTLFI RCNIAWCRRR
KTTRLGKYPV LEVIVVTAIT AIIAYPNPYT RQSTSELISE LFNDCGALES SQLCDYINDP
NMTRPVDDIP DRPAGVGVYT AMWQLALALI FKIVVTIFTF GMKIPSGLFI PSMAVGAIAG
RMVGIGVEQL AYHHHDWIIF RNWCRPGADC VTPGLYAMVG AAACLGGVTR MTVSLVVIMF
ELTGGLEYIV PLMAAAVTSK WVADAFGKEG IYEAHIHLNG YPFLDVKDEF THRTLATDVM
RPRRGEPPLS VLTQDSMTVE DVETLIKETD YNGFPVVVSR DSERLIGFAQ RRELILAIKN
ARQRQEGIVS NSIMYFTEEP PELPANSPHP LKLRRILNLS PFTVTDHTPM ETVVDIFRKL
GLRQCLVTRS GRLLGIITKK DVLRHMAQMA NQDPESIMFN
