CLCN5_HUMAN
ID CLCN5_HUMAN Reviewed; 816 AA.
AC P51795; A1L475; B3KPN6; Q5JQD5; Q7RTN8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 12-AUG-2020, sequence version 2.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=H(+)/Cl(-) exchange transporter 5 {ECO:0000305};
DE AltName: Full=Chloride channel protein 5;
DE Short=ClC-5;
DE AltName: Full=Chloride transporter ClC-5;
GN Name=CLCN5 {ECO:0000312|HGNC:HGNC:2023}; Synonyms=CLCK2;
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 2).
RC TISSUE=Kidney;
RX PubMed=8575751; DOI=10.1006/geno.1995.9960;
RA Fisher S.E., van Bakel I., Lloyd S.E., Pearce S.H.S., Thakker R.V.,
RA Craig I.W.;
RT "Cloning and characterization of CLCN5, the human kidney chloride channel
RT gene implicated in Dent disease (an X-linked hereditary nephrolithiasis).";
RL Genomics 29:598-606(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 557-816.
RC TISSUE=Kidney;
RX PubMed=7874126;
RA Fisher S., Black G.C.M., Lloyd S.E., Hatchwell E., Wrong O., Thakker R.V.,
RA Craig I.W.;
RT "Isolation and partial characterization of a chloride channel gene which is
RT expressed in kidney and is a candidate for Dent's disease (an X-linked
RT hereditary nephrolithiasis).";
RL Hum. Mol. Genet. 3:2053-2059(1994).
RN [6]
RP IDENTIFICATION (ISOFORM 1), AND ALTERNATIVE SPLICING.
RX PubMed=12886045; DOI=10.1159/000071883;
RA Ludwig M., Waldegger S., Nuutinen M., Bokenkamp A., Reissinger A.,
RA Steckelbroeck S., Utsch B.;
RT "Four additional CLCN5 exons encode a widely expressed novel long CLC-5
RT isoform but fail to explain Dent's phenotype in patients without mutations
RT in the short variant.";
RL Kidney Blood Press. Res. 26:176-184(2003).
RN [7]
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 [8]
RP INTERACTION WITH NEDD4 AND NEDD4L, UBIQUITINATION, AND MUTAGENESIS OF
RP TYR-742.
RX PubMed=15489223; DOI=10.1074/jbc.m411491200;
RA Hryciw D.H., Ekberg J., Lee A., Lensink I.L., Kumar S., Guggino W.B.,
RA Cook D.I., Pollock C.A., Poronnik P.;
RT "Nedd4-2 functionally interacts with ClC-5: involvement in constitutive
RT albumin endocytosis in proximal tubule cells.";
RL J. Biol. Chem. 279:54996-55007(2004).
RN [9]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20466723; DOI=10.1074/jbc.m110.125971;
RA Neagoe I., Stauber T., Fidzinski P., Bergsdorf E.Y., Jentsch T.J.;
RT "The late endosomal ClC-6 mediates proton/chloride countertransport in
RT heterologous plasma membrane expression.";
RL J. Biol. Chem. 285:21689-21697(2010).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 640-816 IN COMPLEXES WITH ATP AND
RP ADP, AND MUTAGENESIS OF GLU-281; TYR-687; SER-688 AND ASP-797.
RX PubMed=17195847; DOI=10.1038/nsmb1188;
RA Meyer S., Savaresi S., Forster I.C., Dutzler R.;
RT "Nucleotide recognition by the cytoplasmic domain of the human chloride
RT transporter ClC-5.";
RL Nat. Struct. Mol. Biol. 14:60-67(2007).
RN [12]
RP VARIANT XLRHR LEU-314, VARIANT XRN GLU-576, AND VARIANTS DENT1 ARG-270 AND
RP PRO-590.
RX PubMed=8559248; DOI=10.1038/379445a0;
RA Lloyd S.E., Pearce S.H.S., Fisher S.E., Steinmeyer K., Schwappach B.,
RA Schelnman S.J., Harding B., Bolino A., Devoto M., Goodyer P.,
RA Rigden S.P.A., Wrong O., Jentsch T.J., Craig I.W., Thakker R.V.;
RT "A common molecular basis for three inherited kidney stone diseases.";
RL Nature 379:445-449(1996).
RN [13]
RP VARIANT DENT1 LEU-314.
RX PubMed=9187673; DOI=10.1007/s004390050448;
RA Oudet C., Martin-Coignard D., Pannetier S., Praud E., Champion G.,
RA Hanauer A.;
RT "A second family with XLRH displays the mutation S244L in the CLCN5 gene.";
RL Hum. Genet. 99:781-784(1997).
RN [14]
RP VARIANTS DENT1 HIS-100 INS; VAL-127; ARG-582 AND ASP-597.
RX PubMed=9259268; DOI=10.1093/hmg/6.8.1233;
RA Lloyd S.E., Guenther W., Pearce S.H.S., Thomson A., Bianchi M.L., Bosio M.,
RA Craig I.W., Fisher S.E., Scheinman S.J., Wrong O., Jentsch T.J.,
RA Thakker R.V.;
RT "Characterisation of renal chloride channel, CLCN5, mutations in
RT hypercalciuric nephrolithiasis (kidney stones) disorders.";
RL Hum. Mol. Genet. 6:1233-1239(1997).
RN [15]
RP VARIANT LMWPHN PRO-350.
RX PubMed=9062355; DOI=10.1172/jci119262;
RA Lloyd S.E., Pearce S.H.S., Guenther W., Kawaguchi H., Igarashi T.,
RA Jentsch T.J., Thakker R.V.;
RT "Idiopathic low molecular weight proteinuria associated with hypercalciuric
RT nephrocalcinosis in Japanese children is due to mutations of the renal
RT chloride channel (CLCN5).";
RL J. Clin. Invest. 99:967-974(1997).
RN [16]
RP VARIANT DENT1 VAL-127.
RX PubMed=9602200; DOI=10.1016/s0022-3476(98)70318-x;
RA Schurman S.J., Norden A.G., Scheinman S.J.;
RT "X-linked recessive nephrolithiasis: presentation and diagnosis in
RT children.";
RL J. Pediatr. 132:859-862(1998).
RN [17]
RP VARIANTS DENT1 ARG-340 AND PHE-348, AND CHARACTERIZATION OF VARIANTS DENT1
RP ARG-340 AND PHE-348.
RX PubMed=9853249; DOI=10.1046/j.1523-1755.1998.00203.x;
RA Igarashi T., Gunther W., Sekine T., Inatomi J., Shiraga H., Takahashi S.,
RA Suzuki J., Tsuru N., Yanagihara T., Shimazu M., Jentsch T.J., Thakker R.V.;
RT "Functional characterization of renal chloride channel, CLCN5, mutations
RT associated with Dent'sJapan disease.";
RL Kidney Int. 54:1850-1856(1998).
RN [18]
RP VARIANT LMWPHN LYS-594.
RX PubMed=11136179; DOI=10.1016/s0272-6386(01)80067-6;
RA Takemura T., Hino S., Ikeda M., Okada M., Igarashi T., Inatomi J.,
RA Yoshioka K.;
RT "Identification of two novel mutations in the CLCN5 gene in Japanese
RT patients with familial idiopathic low molecular weight proteinuria
RT (Japanese Dent's disease).";
RL Am. J. Kidney Dis. 37:138-143(2001).
RN [19]
RP VARIANTS DENT1 ARG-291; LEU-314; ALA-337; GLY-340; ASP-532; ARG-583;
RP TRP-586; ASN-615; GLU-616 AND SER-727.
RX PubMed=15086899; DOI=10.1111/j.1523-1755.2004.00571.x;
RA Hoopes R.R. Jr., Raja K.M., Koich A., Hueber P., Reid R., Knohl S.J.,
RA Scheinman S.J.;
RT "Evidence for genetic heterogeneity in Dent's disease.";
RL Kidney Int. 65:1615-1620(2004).
RN [20]
RP VARIANT DENT1 VAL-330.
RX PubMed=16247550; DOI=10.1007/s10038-005-0317-x;
RA Tosetto E., Graziotto R., Artifoni L., Nachtigal J., Cascone C., Conz P.,
RA Piva M., Dell'Aquila R., De Paoli Vitali E., Citron L., Nalesso F.,
RA Antonello A., Vertolli U., Zagatti R., Lupo A., D'Angelo A., Anglani F.,
RA Gambaro G.;
RT "Dent's disease and prevalence of renal stones in dialysis patients in
RT Northeastern Italy.";
RL J. Hum. Genet. 51:25-30(2006).
RN [21]
RP VARIANTS DENT1 LEU-314; VAL-330; GLU-337 DEL; CYS-342 AND LYS-410.
RX PubMed=16822791; DOI=10.1093/ndt/gfl274;
RA Tosetto E., Ghiggeri G.M., Emma F., Barbano G., Carrea A., Vezzoli G.,
RA Torregrossa R., Cara M., Ripanti G., Ammenti A., Peruzzi L., Murer L.,
RA Ratsch I.M., Citron L., Gambaro G., D'angelo A., Anglani F.;
RT "Phenotypic and genetic heterogeneity in Dent's disease -- the results of
RT an Italian collaborative study.";
RL Nephrol. Dial. Transplant. 21:2452-2463(2006).
RN [22]
RP VARIANTS DENT1 LEU-314 AND VAL-330.
RX PubMed=16416111; DOI=10.1007/s00240-005-0005-5;
RA Anglani F., Bernich P., Tosetto E., Cara M., Lupo A., Nalesso F.,
RA D'Angelo A., Gambaro G.;
RT "Family history may be misleading in the diagnosis of Dent's disease.";
RL Urol. Res. 34:61-63(2006).
RN [23]
RP VARIANTS DENT1 ARG-289; LEU-343 AND GLY-617.
RX PubMed=17262170; DOI=10.1007/s10038-007-0112-y;
RA Ramos-Trujillo E., Gonzalez-Acosta H., Flores C., Garcia-Nieto V.,
RA Guillen E., Gracia S., Vicente C., Espinosa L., Maseda M.A., Santos F.,
RA Camacho J.A., Claverie-Martin F.;
RT "A missense mutation in the chloride/proton ClC-5 antiporter gene results
RT in increased expression of an alternative mRNA form that lacks exons 10 and
RT 11. Identification of seven new CLCN5 mutations in patients with Dent's
RT disease.";
RL J. Hum. Genet. 52:255-261(2007).
RN [24]
RP VARIANT DENT1 ARG-403.
RX PubMed=18025833; DOI=10.1159/000111253;
RA Tanuma A., Sato H., Takeda T., Hosojima M., Obayashi H., Hama H., Iino N.,
RA Hosaka K., Kaseda R., Imai N., Ueno M., Yamazaki M., Sakimura K., Gejyo F.,
RA Saito A.;
RT "Functional characterization of a novel missense CLCN5 mutation causing
RT alterations in proximal tubular endocytic machinery in Dent's disease.";
RL Nephron Physiol. 107:87-97(2007).
RN [25]
RP CHARACTERIZATION OF VARIANTS DENT1 VAL-127; ARG-340; GLU-583; TRP-586 AND
RP ASP-597, CHARACTERIZATION OF VARIANTS LMWPHN PRO-350 AND LYS-594, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19019917; DOI=10.1152/ajprenal.90526.2008;
RA Smith A.J., Reed A.A., Loh N.Y., Thakker R.V., Lippiat J.D.;
RT "Characterization of Dent's disease mutations of CLC-5 reveals a
RT correlation between functional and cell biological consequences and protein
RT structure.";
RL Am. J. Physiol. 296:F390-F397(2009).
RN [26]
RP VARIANTS DENT1 ASP-249; LEU-273; ALA-282 AND PRO-539, AND CHARACTERIZATION
RP OF VARIANTS DENT1 ASP-249; ARG-270; LEU-273; ALA-282; ARG-289; ARG-291 AND
RP PRO-539.
RX PubMed=19657328; DOI=10.1038/ki.2009.305;
RA Grand T., Mordasini D., L'Hoste S., Pennaforte T., Genete M.,
RA Biyeyeme M.J., Vargas-Poussou R., Blanchard A., Teulon J., Lourdel S.;
RT "Novel CLCN5 mutations in patients with Dent's disease result in altered
RT ion currents or impaired exchanger processing.";
RL Kidney Int. 76:999-1005(2009).
RN [27]
RP CHARACTERIZATION OF VARIANTS DENT1 PRO-295; VAL-330; CYS-342; PHE-348;
RP LYS-410; ARG-583; GLU-616 AND GLY-617, AND CHARACTERIZATION OF VARIANT
RP XLRHR LEU-314.
RX PubMed=21305656; DOI=10.1002/humu.21467;
RA Grand T., L'Hoste S., Mordasini D., Defontaine N., Keck M., Pennaforte T.,
RA Genete M., Laghmani K., Teulon J., Lourdel S.;
RT "Heterogeneity in the processing of CLCN5 mutants related to Dent
RT disease.";
RL Hum. Mutat. 32:476-483(2011).
CC -!- FUNCTION: Proton-coupled chloride transporter. Functions as antiport
CC system and exchanges chloride ions against protons (PubMed:20466723).
CC Important for normal acidification of the endosome lumen. May play an
CC important role in renal tubular function. The CLC channel family
CC contains both chloride channels and proton-coupled anion transporters
CC that exchange chloride or another anion for protons. The absence of
CC conserved gating glutamate residues is typical for family members that
CC function as channels (Probable). {ECO:0000269|PubMed:20466723,
CC ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 chloride(in) + H(+)(out) = 2 chloride(out) + H(+)(in);
CC Xref=Rhea:RHEA:29567, ChEBI:CHEBI:15378, ChEBI:CHEBI:17996;
CC Evidence={ECO:0000305|PubMed:20466723};
CC -!- SUBUNIT: Interacts with NEDD4 and NEDD4L.
CC {ECO:0000269|PubMed:15489223}.
CC -!- INTERACTION:
CC P51795; P51795: CLCN5; NbExp=2; IntAct=EBI-13619183, EBI-13619183;
CC P51795; O15066: KIF3B; NbExp=6; IntAct=EBI-13619183, EBI-3931791;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane
CC {ECO:0000269|PubMed:19019917}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:19019917}. Endosome membrane
CC {ECO:0000269|PubMed:19019917}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:19019917}. Cell membrane
CC {ECO:0000269|PubMed:19019917}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:19019917}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P51795-2; Sequence=Displayed;
CC Name=2;
CC IsoId=P51795-1; Sequence=VSP_060654;
CC -!- TISSUE SPECIFICITY: Kidney. Moderately expressed in aortic vascular
CC smooth muscle and endothelial cells, and at a slightly higher level in
CC the coronary vascular smooth muscle. {ECO:0000269|PubMed:10198195}.
CC -!- PTM: Ubiquitinated by NEDD4L in the presence of albumin; which promotes
CC endocytosis and proteasomal degradation. {ECO:0000269|PubMed:15489223}.
CC -!- DISEASE: Hypophosphatemic rickets, X-linked recessive (XLRHR)
CC [MIM:300554]: A renal disease belonging to the 'Dent disease complex',
CC a group of disorders characterized by proximal renal tubular defect,
CC hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum
CC of phenotypic features is remarkably similar in the various disorders,
CC except for differences in the severity of bone deformities and renal
CC impairment. XLRH patients present with rickets or osteomalacia,
CC hypophosphatemia due to decreased renal tubular phosphate reabsorption,
CC hypercalciuria, and low molecular weight proteinuria. Patients develop
CC nephrocalcinosis with progressive renal failure in adulthood. Female
CC carriers may have asymptomatic hypercalciuria or hypophosphatemia only.
CC {ECO:0000269|PubMed:21305656, ECO:0000269|PubMed:8559248}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Dent disease 1 (DENT1) [MIM:300009]: An X-linked recessive
CC renal disease belonging to the 'Dent disease complex', a group of
CC disorders characterized by proximal renal tubular defect,
CC hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum
CC of phenotypic features is remarkably similar in the various disorders,
CC except for differences in the severity of bone deformities and renal
CC impairment. DENT1 patients manifest hypercalciuria, hypophosphatemia,
CC aminoaciduria, nephrocalcinosis and nephrolithiasis, renal
CC insufficiency leading to renal failure in adulthood, rickets (33% of
CC patients) and osteomalacia. {ECO:0000269|PubMed:15086899,
CC ECO:0000269|PubMed:16247550, ECO:0000269|PubMed:16416111,
CC ECO:0000269|PubMed:16822791, ECO:0000269|PubMed:17262170,
CC ECO:0000269|PubMed:18025833, ECO:0000269|PubMed:19019917,
CC ECO:0000269|PubMed:19657328, ECO:0000269|PubMed:21305656,
CC ECO:0000269|PubMed:8559248, ECO:0000269|PubMed:9187673,
CC ECO:0000269|PubMed:9259268, ECO:0000269|PubMed:9602200,
CC ECO:0000269|PubMed:9853249}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Nephrolithiasis, X-linked recessive, with renal failure (XRN)
CC [MIM:310468]: An X-linked recessive renal disease belonging to the
CC 'Dent disease complex', a group of disorders characterized by proximal
CC renal tubular defect, hypercalciuria, nephrocalcinosis and renal
CC insufficiency. The spectrum of phenotypic features is remarkably
CC similar in the various disorders, except for differences in the
CC severity of bone deformities and renal impairment. XRN patients present
CC with hypercalciuria, nephrocalcinosis, renal stones and renal
CC insufficiency. Patients lack urinary acidification defects, rickets,
CC and osteomalacia. {ECO:0000269|PubMed:8559248}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Low molecular weight proteinuria with hypercalciuria and
CC nephrocalcinosis (LMWPHN) [MIM:308990]: An X-linked renal disease
CC belonging to the 'Dent disease complex', a group of disorders
CC characterized by proximal renal tubular defect, hypercalciuria,
CC nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic
CC features is remarkably similar in the various disorders, except for
CC differences in the severity of bone deformities and renal impairment.
CC LMWPHN is a slowly progressive disorder. Patients tend to have
CC hypercalciuric nephrocalcinosis without rickets or renal failure.
CC {ECO:0000269|PubMed:11136179, ECO:0000269|PubMed:19019917,
CC ECO:0000269|PubMed:9062355}. 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 5/CLCN5 subfamily. {ECO:0000305}.
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DR EMBL; X91906; CAA63000.1; -; mRNA.
DR EMBL; AK056560; BAG51748.1; -; mRNA.
DR EMBL; FO393402; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC130429; AAI30430.1; -; mRNA.
DR EMBL; BC130431; AAI30432.1; -; mRNA.
DR EMBL; X81836; CAA57430.1; -; mRNA.
DR EMBL; BK000969; DAA01544.1; -; mRNA.
DR CCDS; CCDS14328.1; -. [P51795-1]
DR CCDS; CCDS48115.1; -. [P51795-2]
DR PIR; I37277; I37277.
DR RefSeq; NP_000075.1; NM_000084.4. [P51795-1]
DR RefSeq; NP_001121370.1; NM_001127898.3. [P51795-2]
DR RefSeq; NP_001121371.1; NM_001127899.3. [P51795-2]
DR RefSeq; NP_001269092.1; NM_001282163.1.
DR PDB; 2J9L; X-ray; 2.30 A; A/B/C/D/E/F=641-816.
DR PDB; 2JA3; X-ray; 3.05 A; A/B/C/D/E/F=641-816.
DR PDBsum; 2J9L; -.
DR PDBsum; 2JA3; -.
DR AlphaFoldDB; P51795; -.
DR SMR; P51795; -.
DR BioGRID; 107598; 18.
DR DIP; DIP-29263N; -.
DR IntAct; P51795; 4.
DR STRING; 9606.ENSP00000365256; -.
DR GlyGen; P51795; 2 sites.
DR iPTMnet; P51795; -.
DR PhosphoSitePlus; P51795; -.
DR BioMuta; CLCN5; -.
DR EPD; P51795; -.
DR jPOST; P51795; -.
DR MassIVE; P51795; -.
DR MaxQB; P51795; -.
DR PaxDb; P51795; -.
DR PeptideAtlas; P51795; -.
DR PRIDE; P51795; -.
DR ProteomicsDB; 56391; -. [P51795-1]
DR ProteomicsDB; 56392; -. [P51795-2]
DR ABCD; P51795; 2 sequenced antibodies.
DR Antibodypedia; 396; 202 antibodies from 30 providers.
DR DNASU; 1184; -.
DR Ensembl; ENST00000307367.2; ENSP00000304257.2; ENSG00000171365.17. [P51795-1]
DR Ensembl; ENST00000376088.7; ENSP00000365256.3; ENSG00000171365.17. [P51795-2]
DR Ensembl; ENST00000376091.8; ENSP00000365259.3; ENSG00000171365.17. [P51795-2]
DR Ensembl; ENST00000376108.7; ENSP00000365276.3; ENSG00000171365.17. [P51795-1]
DR Ensembl; ENST00000642885.1; ENSP00000496632.1; ENSG00000171365.17. [P51795-1]
DR GeneID; 1184; -.
DR KEGG; hsa:1184; -.
DR MANE-Select; ENST00000376091.8; ENSP00000365259.3; NM_001127898.4; NP_001121370.1.
DR UCSC; uc004doq.2; human. [P51795-2]
DR CTD; 1184; -.
DR DisGeNET; 1184; -.
DR GeneCards; CLCN5; -.
DR GeneReviews; CLCN5; -.
DR HGNC; HGNC:2023; CLCN5.
DR HPA; ENSG00000171365; Group enriched (epididymis, kidney, liver).
DR MalaCards; CLCN5; -.
DR MIM; 300008; gene.
DR MIM; 300009; phenotype.
DR MIM; 300554; phenotype.
DR MIM; 308990; phenotype.
DR MIM; 310468; phenotype.
DR neXtProt; NX_P51795; -.
DR OpenTargets; ENSG00000171365; -.
DR Orphanet; 93622; Dent disease type 1.
DR PharmGKB; PA26550; -.
DR VEuPathDB; HostDB:ENSG00000171365; -.
DR eggNOG; KOG0475; Eukaryota.
DR GeneTree; ENSGT00940000153763; -.
DR HOGENOM; CLU_003181_2_1_1; -.
DR InParanoid; P51795; -.
DR OMA; CLDWTPW; -.
DR OrthoDB; 271925at2759; -.
DR PhylomeDB; P51795; -.
DR TreeFam; TF313867; -.
DR PathwayCommons; P51795; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; P51795; -.
DR BioGRID-ORCS; 1184; 8 hits in 705 CRISPR screens.
DR ChiTaRS; CLCN5; human.
DR EvolutionaryTrace; P51795; -.
DR GeneWiki; CLCN5; -.
DR GenomeRNAi; 1184; -.
DR Pharos; P51795; Tbio.
DR PRO; PR:P51795; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; P51795; protein.
DR Bgee; ENSG00000171365; Expressed in renal medulla and 141 other tissues.
DR ExpressionAtlas; P51795; baseline and differential.
DR Genevisible; P51795; HS.
DR GO; GO:0045177; C:apical part of cell; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005769; C:early endosome; IBA:GO_Central.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0008021; C:synaptic vesicle; IBA:GO_Central.
DR GO; GO:0015297; F:antiporter activity; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0015299; F:solute:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0005247; F:voltage-gated chloride channel activity; IMP:UniProtKB.
DR GO; GO:0006821; P:chloride transport; IMP:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:Ensembl.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0003014; P:renal system process; IMP:UniProtKB.
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; IPR002247; Cl_channel-5.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00654; Voltage_CLC; 1.
DR PRINTS; PR00762; CLCHANNEL.
DR PRINTS; PR01116; CLCHANNEL5.
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 3D-structure; Alternative splicing; Antiport; ATP-binding; CBS domain;
KW Cell membrane; Chloride; Disease variant; Endosome; Golgi apparatus;
KW Ion transport; Membrane; Nucleotide-binding; Reference proteome; Repeat;
KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation.
FT CHAIN 1..816
FT /note="H(+)/Cl(-) exchange transporter 5"
FT /id="PRO_0000094446"
FT TOPO_DOM 1..124
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 125..162
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 208..231
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 240..247
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 256..275
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 281..300
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 312..324
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 328..336
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 348..366
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 389..415
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 422..442
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 498..518
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 523..542
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 570..584
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 585..587
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT INTRAMEM 588..599
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 600..604
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT TRANSMEM 605..622
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TOPO_DOM 623..816
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT DOMAIN 656..720
FT /note="CBS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT DOMAIN 752..812
FT /note="CBS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT REGION 1..26
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 237..241
FT /note="Selectivity filter part_1"
FT /evidence="ECO:0000250"
FT MOTIF 279..283
FT /note="Selectivity filter part_2"
FT /evidence="ECO:0000250"
FT MOTIF 523..527
FT /note="Selectivity filter part_3"
FT /evidence="ECO:0000250"
FT COMPBIAS 10..26
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 238
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 525
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 628
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 666
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:17195847,
FT ECO:0007744|PDB:2J9L"
FT BINDING 687..689
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:17195847,
FT ECO:0007744|PDB:2J9L"
FT BINDING 794..797
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:17195847,
FT ECO:0007744|PDB:2J9L"
FT SITE 281
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 /evidence="ECO:0000250"
FT SITE 338
FT /note="Mediates proton transfer from the protein to the
FT inner aqueous phase"
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..70
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_060654"
FT VARIANT 100
FT /note="R -> RH (in DENT1)"
FT /evidence="ECO:0000269|PubMed:9259268"
FT /id="VAR_001615"
FT VARIANT 127
FT /note="G -> V (in DENT1; alters targeting to endosomes;
FT dbSNP:rs151340629)"
FT /evidence="ECO:0000269|PubMed:19019917,
FT ECO:0000269|PubMed:9259268, ECO:0000269|PubMed:9602200"
FT /id="VAR_001616"
FT VARIANT 212
FT /note="M -> I (in dbSNP:rs34800648)"
FT /id="VAR_048694"
FT VARIANT 249
FT /note="G -> D (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional)"
FT /evidence="ECO:0000269|PubMed:19657328"
FT /id="VAR_065591"
FT VARIANT 270
FT /note="L -> R (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional;
FT dbSNP:rs151340622)"
FT /evidence="ECO:0000269|PubMed:19657328,
FT ECO:0000269|PubMed:8559248"
FT /id="VAR_001617"
FT VARIANT 273
FT /note="S -> L (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional)"
FT /evidence="ECO:0000269|PubMed:19657328"
FT /id="VAR_065592"
FT VARIANT 282
FT /note="G -> A (in DENT1; trafficks normally to the cell
FT surface and to early endosomes; endergoes complex
FT glycosylation at the cell surface like wild-type protein
FT but exhibits significant reductions in outwardly rectifying
FT ion currents)"
FT /evidence="ECO:0000269|PubMed:19657328"
FT /id="VAR_065593"
FT VARIANT 289
FT /note="C -> R (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional)"
FT /evidence="ECO:0000269|PubMed:17262170,
FT ECO:0000269|PubMed:19657328"
FT /id="VAR_065594"
FT VARIANT 291
FT /note="C -> R (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional)"
FT /evidence="ECO:0000269|PubMed:15086899,
FT ECO:0000269|PubMed:19657328"
FT /id="VAR_065595"
FT VARIANT 295
FT /note="L -> P (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional;
FT dbSNP:rs273585645)"
FT /evidence="ECO:0000269|PubMed:21305656"
FT /id="VAR_065596"
FT VARIANT 314
FT /note="S -> L (in XLRHR; trafficks normally to the cell
FT surface and to early endosomes; displays complex
FT glycosylation at the cell surface like wild-type protein;
FT exhibits reduced current; dbSNP:rs151340626)"
FT /evidence="ECO:0000269|PubMed:15086899,
FT ECO:0000269|PubMed:16416111, ECO:0000269|PubMed:16822791,
FT ECO:0000269|PubMed:21305656, ECO:0000269|PubMed:8559248,
FT ECO:0000269|PubMed:9187673"
FT /id="VAR_001618"
FT VARIANT 330
FT /note="G -> V (in DENT1; delayed in processing of the
FT protein and decrease in the stability of the mature complex
FT glycosylated form causing lower cell surface expression;
FT the early endosome distribution is normal; shows abolished
FT current at the plasma membrane; dbSNP:rs151340630)"
FT /evidence="ECO:0000269|PubMed:16247550,
FT ECO:0000269|PubMed:16416111, ECO:0000269|PubMed:16822791,
FT ECO:0000269|PubMed:21305656"
FT /id="VAR_065597"
FT VARIANT 337
FT /note="E -> A (in DENT1)"
FT /evidence="ECO:0000269|PubMed:15086899"
FT /id="VAR_065598"
FT VARIANT 337
FT /note="Missing (in DENT1)"
FT /evidence="ECO:0000269|PubMed:16822791"
FT /id="VAR_065599"
FT VARIANT 340
FT /note="S -> G (in DENT1)"
FT /evidence="ECO:0000269|PubMed:15086899"
FT /id="VAR_065600"
FT VARIANT 340
FT /note="S -> R (in DENT1; retained in the endoplasmic
FT reticulum; alters protein stability; associated with an
FT abolition of chloride current)"
FT /evidence="ECO:0000269|PubMed:19019917,
FT ECO:0000269|PubMed:9853249"
FT /id="VAR_065601"
FT VARIANT 342
FT /note="Y -> C (in DENT1; trafficks normally to the cell
FT surface and to early endosomes and displays complex
FT glycosylation at the cell surface like wild-type protein;
FT exhibits no current; dbSNP:rs273585644)"
FT /evidence="ECO:0000269|PubMed:16822791,
FT ECO:0000269|PubMed:21305656"
FT /id="VAR_065602"
FT VARIANT 343
FT /note="F -> L (in DENT1)"
FT /evidence="ECO:0000269|PubMed:17262170"
FT /id="VAR_065603"
FT VARIANT 348
FT /note="L -> F (in DENT1; associated with a marked reduction
FT to about 30% of wild-type chloride currents; no significant
FT differences between the expression of the mutated and wild-
FT type protein; dbSNP:rs273585648)"
FT /evidence="ECO:0000269|PubMed:21305656,
FT ECO:0000269|PubMed:9853249"
FT /id="VAR_065604"
FT VARIANT 350
FT /note="R -> P (in LMWPHN; 70% reduction in chloride
FT transport activity and alters targeting to endosomes;
FT dbSNP:rs151340628)"
FT /evidence="ECO:0000269|PubMed:19019917,
FT ECO:0000269|PubMed:9062355"
FT /id="VAR_001619"
FT VARIANT 403
FT /note="G -> R (in DENT1; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:18025833"
FT /id="VAR_075519"
FT VARIANT 410
FT /note="N -> K (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional;
FT dbSNP:rs273585646)"
FT /evidence="ECO:0000269|PubMed:16822791,
FT ECO:0000269|PubMed:21305656"
FT /id="VAR_065605"
FT VARIANT 532
FT /note="G -> D (in DENT1)"
FT /evidence="ECO:0000269|PubMed:15086899"
FT /id="VAR_065606"
FT VARIANT 539
FT /note="L -> P (in DENT1; retained in the endoplasmic
FT reticulum; improperly N-glycosylated and non-functional)"
FT /evidence="ECO:0000269|PubMed:19657328"
FT /id="VAR_065607"
FT VARIANT 576
FT /note="G -> E (in XRN; dbSNP:rs151340625)"
FT /evidence="ECO:0000269|PubMed:8559248"
FT /id="VAR_001620"
FT VARIANT 582
FT /note="G -> R (in DENT1; abolishes the chloride currents)"
FT /evidence="ECO:0000269|PubMed:9259268"
FT /id="VAR_001621"
FT VARIANT 583
FT /note="G -> E (in DENT1; causes retention in the
FT endoplasmic reticulum and alters protein stability; total
FT loss of function)"
FT /evidence="ECO:0000269|PubMed:19019917"
FT /id="VAR_065608"
FT VARIANT 583
FT /note="G -> R (in DENT1; dbSNP:rs273585647)"
FT /evidence="ECO:0000269|PubMed:15086899,
FT ECO:0000269|PubMed:21305656"
FT /id="VAR_065609"
FT VARIANT 586
FT /note="R -> W (in DENT1; causes retention in the
FT endoplasmic reticulum and alters protein stability; total
FT loss of function; dbSNP:rs797044812)"
FT /evidence="ECO:0000269|PubMed:15086899,
FT ECO:0000269|PubMed:19019917"
FT /id="VAR_065610"
FT VARIANT 590
FT /note="S -> P (in DENT1; dbSNP:rs151340623)"
FT /evidence="ECO:0000269|PubMed:8559248"
FT /id="VAR_001622"
FT VARIANT 594
FT /note="I -> K (in LMWPHN; causes retention in the
FT endoplasmic reticulum and alters protein stability; total
FT loss of function)"
FT /evidence="ECO:0000269|PubMed:11136179,
FT ECO:0000269|PubMed:19019917"
FT /id="VAR_065611"
FT VARIANT 597
FT /note="E -> D (in DENT1; abolishes the chloride currents;
FT total loss of function)"
FT /evidence="ECO:0000269|PubMed:19019917,
FT ECO:0000269|PubMed:9259268"
FT /id="VAR_001623"
FT VARIANT 615
FT /note="S -> N (in DENT1)"
FT /evidence="ECO:0000269|PubMed:15086899"
FT /id="VAR_065612"
FT VARIANT 616
FT /note="K -> E (in DENT1; delayed in processing of the
FT protein and decrease in the stability of the mature complex
FT glycosylated form causing lower cell surface expression;
FT the early endosome distribution is normal; shows abolished
FT current at the plasma membrane)"
FT /evidence="ECO:0000269|PubMed:15086899,
FT ECO:0000269|PubMed:21305656"
FT /id="VAR_065613"
FT VARIANT 617
FT /note="W -> G (in DENT1; delayed in processing of the
FT protein and decrease in the stability of the mature complex
FT glycosylated form causing lower cell surface expression;
FT the early endosome distribution is normal; shows reduced
FT current at the plasma membrane; dbSNP:rs273585650)"
FT /evidence="ECO:0000269|PubMed:17262170,
FT ECO:0000269|PubMed:21305656"
FT /id="VAR_065614"
FT VARIANT 727
FT /note="T -> S (in DENT1; dbSNP:rs144207967)"
FT /evidence="ECO:0000269|PubMed:15086899"
FT /id="VAR_065615"
FT MUTAGEN 281
FT /note="E->A: Abolishes proton transport, but not chloride
FT transport."
FT /evidence="ECO:0000269|PubMed:17195847"
FT MUTAGEN 687
FT /note="Y->A: Strongly decreased affinity for ATP, but no
FT effect on chloride transport."
FT /evidence="ECO:0000269|PubMed:17195847"
FT MUTAGEN 688
FT /note="S->A: No effect ATP binding or chloride transport."
FT /evidence="ECO:0000269|PubMed:17195847"
FT MUTAGEN 742
FT /note="Y->A: Abolishes interaction with NEDD4 and NEDD4L."
FT /evidence="ECO:0000269|PubMed:15489223"
FT MUTAGEN 797
FT /note="D->A: Strongly decreased affinity for ATP, but no
FT effect on chloride transport."
FT /evidence="ECO:0000269|PubMed:17195847"
FT CONFLICT 802
FT /note="I -> V (in Ref. 2; BAG51748)"
FT /evidence="ECO:0000305"
FT HELIX 652..655
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 656..658
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 668..671
FT /evidence="ECO:0007829|PDB:2J9L"
FT HELIX 675..684
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 688..694
FT /evidence="ECO:0007829|PDB:2J9L"
FT TURN 696..698
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 700..706
FT /evidence="ECO:0007829|PDB:2J9L"
FT HELIX 707..718
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 729..731
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 733..735
FT /evidence="ECO:0007829|PDB:2J9L"
FT HELIX 750..752
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 753..756
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 759..761
FT /evidence="ECO:0007829|PDB:2J9L"
FT HELIX 766..776
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 779..785
FT /evidence="ECO:0007829|PDB:2J9L"
FT STRAND 788..794
FT /evidence="ECO:0007829|PDB:2J9L"
FT HELIX 795..805
FT /evidence="ECO:0007829|PDB:2J9L"
SQ SEQUENCE 816 AA; 90785 MW; C9C63CC222959F35 CRC64;
MAMWQGAMDN RGFQQGSFSS FQNSSSDEDL MDIPATAMDF SMRDDVPPLD REVGEDKSYN
GGGIGSSNRI MDFLEEPIPG VGTYDDFNTI DWVREKSRDR DRHREITNKS KESTWALIHS
VSDAFSGWLL MLLIGLLSGS LAGLIDISAH WMTDLKEGIC TGGFWFNHEH CCWNSEHVTF
EERDKCPEWN SWSQLIISTD EGAFAYIVNY FMYVLWALLF AFLAVSLVKV FAPYACGSGI
PEIKTILSGF IIRGYLGKWT LVIKTITLVL AVSSGLSLGK EGPLVHVACC CGNILCHCFN
KYRKNEAKRR EVLSAAAAAG VSVAFGAPIG GVLFSLEEVS YYFPLKTLWR SFFAALVAAF
TLRSINPFGN SRLVLFYVEF HTPWHLFELV PFILLGIFGG LWGALFIRTN IAWCRKRKTT
QLGKYPVIEV LVVTAITAIL AFPNEYTRMS TSELISELFN DCGLLDSSKL CDYENRFNTS
KGGELPDRPA GVGVYSAMWQ LALTLILKIV ITIFTFGMKI PSGLFIPSMA VGAIAGRLLG
VGMEQLAYYH QEWTVFNSWC SQGADCITPG LYAMVGAAAC LGGVTRMTVS LVVIMFELTG
GLEYIVPLMA AAMTSKWVAD ALGREGIYDA HIRLNGYPFL EAKEEFAHKT LAMDVMKPRR
NDPLLTVLTQ DSMTVEDVET IISETTYSGF PVVVSRESQR LVGFVLRRDL IISIENARKK
QDGVVSTSII YFTEHSPPLP PYTPPTLKLR NILDLSPFTV TDLTPMEIVV DIFRKLGLRQ
CLVTHNGRLL GIITKKDVLK HIAQMANQDP DSILFN
