S12A3_HUMAN
ID S12A3_HUMAN Reviewed; 1021 AA.
AC P55017; A8MSJ2; C9JNN9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Solute carrier family 12 member 3;
DE AltName: Full=Na-Cl cotransporter;
DE Short=NCC;
DE AltName: Full=Na-Cl symporter;
DE AltName: Full=Thiazide-sensitive sodium-chloride cotransporter;
GN Name=SLC12A3; Synonyms=NCC, TSC;
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), VARIANTS GTLMNS TRP-209; GLY-264;
RP LEU-349; ARG-421; ASN-486; CYS-496; SER-561 DEL; VAL-588; VAL-630; HIS-655;
RP LEU-655; ARG-741; PRO-850 AND GLN-955, VARIANT THR-728, AND FUNCTION.
RX PubMed=8528245; DOI=10.1038/ng0196-24;
RA Simon D.B., Nelson-Williams C., Bia M.J., Ellison D., Karet F.E.,
RA Molina A.M., Vaara I., Iwata F., Cushner H.M., Koolen M., Gainza F.J.,
RA Gitelman H.J., Lifton R.P.;
RT "Gitelman's variant of Bartter's syndrome, inherited hypokalaemic
RT alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl
RT cotransporter.";
RL Nat. Genet. 12:24-30(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-264, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=8812482; DOI=10.1006/geno.1996.0388;
RA Mastroianni N., de Fusco M., Zollo M., Arrigo G., Zuffardi O.,
RA Bettinelli A., Ballabio A., Casari G.;
RT "Molecular cloning, expression pattern, and chromosomal localization of the
RT human Na-Cl thiazide-sensitive cotransporter (SLC12A3).";
RL Genomics 35:486-493(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT GLY-264.
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=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [5]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=21613606; DOI=10.1152/ajpcell.00070.2011;
RA Cruz-Rangel S., Melo Z., Vazquez N., Meade P., Bobadilla N.A.,
RA Pasantes-Morales H., Gamba G., Mercado A.;
RT "Similar Effects of all WNK3 Variants upon SLC12 Cotransporters.";
RL Am. J. Physiol. 301:C601-C608(2011).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-91, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
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 [7]
RP TISSUE SPECIFICITY, AND CHARACTERIZATION OF VARIANTS GTLMNS ASP-121;
RP SER-439; CYS-475 AND ARG-1021.
RX PubMed=26099046; DOI=10.1038/nm.3890;
RA Wang J., Sun C., Gerdes N., Liu C., Liao M., Liu J., Shi M.A., He A.,
RA Zhou Y., Sukhova G.K., Chen H., Cheng X.W., Kuzuya M., Murohara T.,
RA Zhang J., Cheng X., Jiang M., Shull G.E., Rogers S., Yang C.L., Ke Q.,
RA Jelen S., Bindels R., Ellison D.H., Jarolim P., Libby P., Shi G.P.;
RT "Interleukin 18 function in atherosclerosis is mediated by the interleukin
RT 18 receptor and the Na-Cl co-transporter.";
RL Nat. Med. 21:820-826(2015).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=29993276; DOI=10.1152/ajprenal.00539.2017;
RA Frische S., Chambrey R., Trepiccione F., Zamani R., Marcussen N.,
RA Alexander R.T., Skjoedt K., Svenningsen P., Dimke H.;
RT "H+-ATPase B1 subunit localizes to thick ascending limb and distal
RT convoluted tubule of rodent and human kidney.";
RL Am. J. Physiol. 315:F429-F444(2018).
RN [9]
RP VARIANTS GTLMNS ASN-62; ASP-186; TRP-209; LEU-349; SER-439; GLU-478;
RP ASN-486; CYS-496; PRO-542; VAL-588 AND ARG-731.
RX PubMed=8900229;
RA Mastroianni N., Bettinelli A., Bianchetti M., Colussi G., De Fusco M.,
RA Sereni F., Ballabio A., Casari G.;
RT "Novel molecular variants of the Na-Cl cotransporter gene are responsible
RT for Gitelman syndrome.";
RL Am. J. Hum. Genet. 59:1019-1026(1996).
RN [10]
RP INTERACTION WITH KLHL3, AND UBIQUITINATION.
RX PubMed=22406640; DOI=10.1038/ng.2218;
RA Louis-Dit-Picard H., Barc J., Trujillano D., Miserey-Lenkei S.,
RA Bouatia-Naji N., Pylypenko O., Beaurain G., Bonnefond A., Sand O.,
RA Simian C., Vidal-Petiot E., Soukaseum C., Mandet C., Broux F., Chabre O.,
RA Delahousse M., Esnault V., Fiquet B., Houillier P., Bagnis C.I., Koenig J.,
RA Konrad M., Landais P., Mourani C., Niaudet P., Probst V., Thauvin C.,
RA Unwin R.J., Soroka S.D., Ehret G., Ossowski S., Caulfield M., Bruneval P.,
RA Estivill X., Froguel P., Hadchouel J., Schott J.J., Jeunemaitre X.;
RT "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion
RT transport in the distal nephron.";
RL Nat. Genet. 44:456-460(2012).
RN [11]
RP VARIANT GTLMNS PRO-623.
RX PubMed=8954067; DOI=10.1210/jcem.81.12.8954067;
RA Takeuchi K., Kure S., Kato T., Taniyama Y., Takahashi N., Ikeda Y., Abe T.,
RA Narisawa K., Muramatsu Y., Abe K.;
RT "Association of a mutation in thiazide-sensitive Na-Cl cotransporter with
RT familial Gitelman's syndrome.";
RL J. Clin. Endocrinol. Metab. 81:4496-4499(1996).
RN [12]
RP VARIANTS GTLMNS TRP-209; PRO-215; THR-226; HIS-261; HIS-560; SER-613;
RP HIS-642; ARG-649; CYS-655; ARG-738; ARG-741; PRO-850 AND CYS-852, AND
RP VARIANTS GLN-904 AND CYS-919.
RX PubMed=9734597; DOI=10.1046/j.1523-1755.1998.00070.x;
RA Lemmink H.H., Knoers N.V.A.M., Karolyi L., van Dijk H., Niaudet P.,
RA Antignac C., Guay-Woodford L.M., Goodyer P.R., Carel J.-C., Hermes A.,
RA Seyberth H.W., Monnens L.A.H., van den Heuvel L.P.W.J.;
RT "Novel mutations in the thiazide-sensitive NaCl cotransporter gene in
RT patients with Gitelman syndrome with predominant localization to the C-
RT terminal domain.";
RL Kidney Int. 54:720-730(1998).
RN [13]
RP VARIANTS GTLMNS PRO-304; SER-439; ARG-731 AND ARG-741, AND VARIANT GLN-904.
RX PubMed=10988270; DOI=10.1161/01.hyp.36.3.389;
RA Melander O., Orho-Melander M., Bengtsson K., Lindblad U., Rastam L.,
RA Groop L., Hulthen U.L.;
RT "Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's
RT syndrome and primary hypertension.";
RL Hypertension 36:389-394(2000).
RN [14]
RP VARIANTS GTLMNS LYS-180; GLU-569; MET-578; CYS-642 AND HIS-849.
RX PubMed=10616841; DOI=10.1681/asn.v11165;
RA Monkawa T., Kurihara I., Kobayashi K., Hayashi M., Saruta T.;
RT "Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients
RT with Gitelman's syndrome.";
RL J. Am. Soc. Nephrol. 11:65-70(2000).
RN [15]
RP VARIANTS GTLMNS PHE-154; LEU-178; GLN-209; ARG-284; VAL-313; TRP-321;
RP TRP-334; CYS-399; LEU-555; LEU-615; GLY-642; LEU-643 AND VAL-729.
RX PubMed=11168953; DOI=10.1046/j.1523-1755.2001.059002710.x;
RA Cruz D.N., Shaer A.J., Bia M.J., Lifton R.P., Simon D.B.;
RT "Gitelman's syndrome revisited: an evaluation of symptoms and health-
RT related quality of life.";
RL Kidney Int. 59:710-717(2001).
RN [16]
RP VARIANT GTLMNS LEU-643, AND VARIANT GLY-264.
RX PubMed=11940055; DOI=10.1046/j.1365-2265.2002.01223.x;
RA Pantanetti P., Arnaldi G., Balercia G., Mantero F., Giacchetti G.;
RT "Severe hypomagnesaemia-induced hypocalcaemia in a patient with Gitelman's
RT syndrome.";
RL Clin. Endocrinol. (Oxf.) 56:413-418(2002).
RN [17]
RP VARIANT GTLMNS PRO-623.
RX PubMed=12008755; DOI=10.1507/endocrj.49.91;
RA Tajima T., Kobayashi Y., Abe S., Takahashi M., Konno M., Nakae J.,
RA Okuhara K., Satoh K., Ishikawa T., Imai T., Fujieda K.;
RT "Two novel mutations of thiazide-sensitive Na-Cl cotrans porter (TSC) gene
RT in two sporadic Japanese patients with Gitelman syndrome.";
RL Endocr. J. 49:91-96(2002).
RN [18]
RP VARIANTS GTLMNS GLN-158; MET-163; ARG-172; TRP-209; VAL-316; VAL-374;
RP GLU-463; THR-464; LEU-615; TRP-615; GLY-642; HIS-642; MET-677; CYS-852;
RP SER-852; GLY-958 AND TYR-985, AND VARIANT GLN-904.
RX PubMed=12112667; DOI=10.1002/humu.9045;
RA Syren M.-L., Tedeschi S., Cesareo L., Bellantuono R., Colussi G.,
RA Procaccio M., Ali A., Domenici R., Malberti F., Sprocati M., Sacco M.,
RA Miglietti N., Edefonti A., Sereni F., Casari G., Coviello D.A.,
RA Bettinelli A.;
RT "Identification of fifteen novel mutations in the SLC12A3 gene encoding the
RT Na-Cl Co-transporter in Italian patients with Gitelman syndrome.";
RL Hum. Mutat. 20:78-78(2002).
RN [19]
RP VARIANTS GTLMNS MET-60; VAL-569; CYS-642 AND HIS-849.
RX PubMed=15069170; DOI=10.1093/ndt/gfh239;
RA Maki N., Komatsuda A., Wakui H., Ohtani H., Kigawa A., Aiba N., Hamai K.,
RA Motegi M., Yamaguchi A., Imai H., Sawada K.;
RT "Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene
RT in Japanese patients with Gitelman's syndrome.";
RL Nephrol. Dial. Transplant. 19:1761-1766(2004).
RN [20]
RP VARIANTS GTLMNS TYR-90; TYR-283 AND HIS-871.
RX PubMed=15687331; DOI=10.1210/jc.2004-1905;
RA Lin S.-H., Shiang J.-C., Huang C.-C., Yang S.-S., Hsu Y.-J., Cheng C.-J.;
RT "Phenotype and genotype analysis in Chinese patients with Gitelman's
RT syndrome.";
RL J. Clin. Endocrinol. Metab. 90:2500-2507(2005).
RN [21]
RP VARIANT GTLMNS ILE-672.
RX PubMed=16429844; DOI=10.5414/cnp65057;
RA Terui K., Shoji M., Yamashiki J., Hirai Y., Ishiguro A., Tsutaya S.,
RA Kageyama K., Yasujima M., Suda T.;
RT "A novel mutation of the thiazide-sensitive sodium chloride cotransporter
RT gene in a Japanese family with Gitelman syndrome.";
RL Clin. Nephrol. 65:57-60(2006).
RN [22]
RP VARIANTS GTLMNS LYS-68; ASN-69; HIS-145; MET-153; ASP-230; ALA-342; LEU-677
RP AND SER-867.
RX PubMed=17654016; DOI=10.1080/10425170701400456;
RA Fava C., Montagnana M., Rosberg L., Burri P., Joensson A., Wanby P.,
RA Wahrenberg H., Hulthen U.L., Aurell M., Guidi G.C., Melander O.;
RT "Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in
RT Swedes.";
RL DNA Seq. 18:395-399(2007).
RN [23]
RP VARIANTS GTLMNS HIS-849 AND HIS-852.
RX PubMed=17873326; DOI=10.1007/s12020-007-0024-9;
RA Aoi N., Nakayama T., Tahira Y., Haketa A., Yabuki M., Sekiyama T.,
RA Nakane C., Mano H., Kawachi H., Sato N., Soma M., Matsumoto K.;
RT "Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter
RT (SLC12A3) gene in patients with Gitelman's syndrome.";
RL Endocrine 31:149-153(2007).
RN [24]
RP VARIANTS GLY-264; THR-728; GLN-904 AND CYS-919, AND CHARACTERIZATION OF
RP VARIANT CYS-919.
RX PubMed=17885550; DOI=10.1097/hjh.0b013e3282a9be1b;
RA Keszei A.P., Tisler A., Backx P.H., Andrulis I.L., Bull S.B., Logan A.G.;
RT "Molecular variants of the thiazide-sensitive Na+-Cl- cotransporter in
RT hypertensive families.";
RL J. Hypertens. 25:2074-2081(2007).
RN [25]
RP VARIANTS GTLMNS MET-60; HIS-62; GLN-83; TRP-83; ASP-121; CYS-135; CYS-145;
RP MET-150; MET-153; PRO-157; LEU-158; MET-163; VAL-166; ARG-172; LEU-178;
RP THR-192; ILE-194; GLN-209; ARG-235; ASN-259; PRO-272; MET-304; PRO-304;
RP VAL-313; TRP-321; TRP-334; GLU-374; MET-382; ILE-392; CYS-399;
RP 433-GLN--CYS-436 DELINS LEU; SER-439; SER-442; ARG-463; THR-464; CYS-475;
RP HIS-489; CYS-507; THR-523; SER-534; LEU-536; GLY-546; LEU-555; ARG-560;
RP ASN-566 DEL; LEU-615; CYS-642; CYS-642; GLY-642; HIS-642; LEU-643; MET-647;
RP HIS-655; LYS-ALA-PHE-TYR-SER-ASP-VAL-ILE-713 INS; VAL-729; ARG-735;
RP ARG-741; LEU-751; THR-824; ASN-839; PHE-849; PRO-850; CYS-852; CYS-862;
RP THR-872; GLN-887; TRP-934; TRP-935; GLN-955; GLY-958; ARG-980; TYR-985;
RP GLN-1009 AND ARG-1021, CHARACTERIZATION OF VARIANT GTLMNS ASP-121; ILE-392;
RP SER-442; CYS-475; HIS-489; LEU-751 AND ARG-1021, FUNCTION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=22009145; DOI=10.1038/ejhg.2011.189;
RA Glaudemans B., Yntema H.G., San-Cristobal P., Schoots J., Pfundt R.,
RA Kamsteeg E.J., Bindels R.J., Knoers N.V., Hoenderop J.G., Hoefsloot L.H.;
RT "Novel NCC mutants and functional analysis in a new cohort of patients with
RT Gitelman syndrome.";
RL Eur. J. Hum. Genet. 20:263-270(2012).
CC -!- FUNCTION: Electroneutral sodium and chloride ion cotransporter. In
CC kidney distal convoluted tubules, key mediator of sodium and chloride
CC reabsorption (PubMed:21613606, PubMed:22009145). Receptor for the pro-
CC inflammatory cytokine IL18. Contributes to IL18-induced cytokine
CC production, including IFNG, IL6, IL18 and CCL2. May act either
CC independently of IL18R1, or in a complex with IL18R1 (By similarity).
CC {ECO:0000250|UniProtKB:P59158, ECO:0000269|PubMed:21613606,
CC ECO:0000269|PubMed:22009145}.
CC -!- ACTIVITY REGULATION: Activated by WNK3. {ECO:0000269|PubMed:21613606}.
CC -!- SUBUNIT: Interacts with KLHL3 (PubMed:22406640). Interacts with IL18R1;
CC this interaction is increased by IL18 treatment (By similarity).
CC {ECO:0000250|UniProtKB:P59158, ECO:0000269|PubMed:22406640}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22009145};
CC Multi-pass membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000250|UniProtKB:P59158}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P55017-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P55017-2; Sequence=VSP_036318;
CC Name=3;
CC IsoId=P55017-3; Sequence=VSP_040100, VSP_036318;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in the kidney (at protein
CC level) (PubMed:29993276, PubMed:8812482). Localizes to the distal
CC convoluted tubules (at protein level)(PubMed:29993276). Not detected in
CC normal aorta, but abundantly expressed in fatty streaks and advanced
CC atherosclerotic lesions (at protein level) (PubMed:26099046).
CC {ECO:0000269|PubMed:26099046, ECO:0000269|PubMed:29993276,
CC ECO:0000269|PubMed:8812482}.
CC -!- PTM: Ubiquitinated; ubiquitination is essential for regulation of
CC endocytosis. The BCR(KLHL3) complex was initially identified as a
CC candidate ubiquitin ligase for SLC12A3 (PubMed:22406640). However, it
CC was later shown that it is not the case. {ECO:0000269|PubMed:22406640}.
CC -!- PTM: Phosphorylated in response to IL18.
CC {ECO:0000250|UniProtKB:P59158}.
CC -!- DISEASE: Gitelman syndrome (GTLMNS) [MIM:263800]: An autosomal
CC recessive disorder characterized by hypokalemic alkalosis in
CC combination with hypomagnesemia, low urinary calcium, and increased
CC renin activity associated with normal blood pressure. Patients are
CC often asymptomatic or present transient periods of muscular weakness
CC and tetany, usually accompanied by abdominal pain, vomiting and fever.
CC The phenotype is highly heterogeneous in terms of age at onset and
CC severity. Cardinal features such as hypocalciuria and hypomagnesemia
CC might also change during the life cycle of a given patient. It has
CC overlapping features with Bartter syndrome.
CC {ECO:0000269|PubMed:10616841, ECO:0000269|PubMed:10988270,
CC ECO:0000269|PubMed:11168953, ECO:0000269|PubMed:11940055,
CC ECO:0000269|PubMed:12008755, ECO:0000269|PubMed:12112667,
CC ECO:0000269|PubMed:15069170, ECO:0000269|PubMed:15687331,
CC ECO:0000269|PubMed:16429844, ECO:0000269|PubMed:17654016,
CC ECO:0000269|PubMed:17873326, ECO:0000269|PubMed:22009145,
CC ECO:0000269|PubMed:26099046, ECO:0000269|PubMed:8528245,
CC ECO:0000269|PubMed:8900229, ECO:0000269|PubMed:8954067,
CC ECO:0000269|PubMed:9734597}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Target of thiazide diuretics used in the treatment of
CC high blood pressure. {ECO:0000305|PubMed:8528245}.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {ECO:0000305}.
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DR EMBL; U44128; AAC50355.1; -; mRNA.
DR EMBL; X91220; CAA62613.1; -; mRNA.
DR EMBL; AK315298; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC012181; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS10770.1; -. [P55017-2]
DR CCDS; CCDS45491.1; -. [P55017-3]
DR CCDS; CCDS58464.1; -. [P55017-1]
DR PIR; G01202; G01202.
DR PIR; PC4180; PC4180.
DR RefSeq; NP_000330.2; NM_000339.2. [P55017-2]
DR RefSeq; NP_001119579.1; NM_001126107.1. [P55017-3]
DR RefSeq; NP_001119580.1; NM_001126108.1. [P55017-1]
DR AlphaFoldDB; P55017; -.
DR SMR; P55017; -.
DR BioGRID; 112448; 20.
DR ELM; P55017; -.
DR IntAct; P55017; 2.
DR STRING; 9606.ENSP00000402152; -.
DR ChEMBL; CHEMBL1876; -.
DR DrugBank; DB00436; Bendroflumethiazide.
DR DrugBank; DB00562; Benzthiazide.
DR DrugBank; DB00880; Chlorothiazide.
DR DrugBank; DB00999; Hydrochlorothiazide.
DR DrugBank; DB00808; Indapamide.
DR DrugBank; DB00524; Metolazone.
DR DrugBank; DB01324; Polythiazide.
DR DrugBank; DB01325; Quinethazone.
DR DrugBank; DB01021; Trichlormethiazide.
DR DrugCentral; P55017; -.
DR TCDB; 2.A.30.1.12; the cation-chloride cotransporter (ccc) family.
DR GlyGen; P55017; 2 sites.
DR iPTMnet; P55017; -.
DR PhosphoSitePlus; P55017; -.
DR BioMuta; SLC12A3; -.
DR DMDM; 313104194; -.
DR jPOST; P55017; -.
DR MassIVE; P55017; -.
DR PaxDb; P55017; -.
DR PeptideAtlas; P55017; -.
DR PRIDE; P55017; -.
DR ProteomicsDB; 56759; -. [P55017-1]
DR ProteomicsDB; 56760; -. [P55017-2]
DR ProteomicsDB; 56761; -. [P55017-3]
DR Antibodypedia; 28680; 259 antibodies from 22 providers.
DR DNASU; 6559; -.
DR Ensembl; ENST00000438926.6; ENSP00000402152.2; ENSG00000070915.10. [P55017-2]
DR Ensembl; ENST00000563236.6; ENSP00000456149.2; ENSG00000070915.10. [P55017-1]
DR Ensembl; ENST00000566786.5; ENSP00000457552.1; ENSG00000070915.10. [P55017-3]
DR GeneID; 6559; -.
DR KEGG; hsa:6559; -.
DR MANE-Select; ENST00000563236.6; ENSP00000456149.2; NM_001126108.2; NP_001119580.2.
DR UCSC; uc002ekd.4; human. [P55017-1]
DR CTD; 6559; -.
DR DisGeNET; 6559; -.
DR GeneCards; SLC12A3; -.
DR HGNC; HGNC:10912; SLC12A3.
DR HPA; ENSG00000070915; Tissue enriched (kidney).
DR MalaCards; SLC12A3; -.
DR MIM; 263800; phenotype.
DR MIM; 600968; gene.
DR neXtProt; NX_P55017; -.
DR OpenTargets; ENSG00000070915; -.
DR Orphanet; 358; Gitelman syndrome.
DR PharmGKB; PA321; -.
DR VEuPathDB; HostDB:ENSG00000070915; -.
DR eggNOG; KOG2083; Eukaryota.
DR GeneTree; ENSGT00940000155044; -.
DR InParanoid; P55017; -.
DR OMA; WNFTDCA; -.
DR OrthoDB; 1152704at2759; -.
DR PhylomeDB; P55017; -.
DR TreeFam; TF313191; -.
DR PathwayCommons; P55017; -.
DR Reactome; R-HSA-426117; Cation-coupled Chloride cotransporters.
DR Reactome; R-HSA-5619087; Defective SLC12A3 causes Gitelman syndrome (GS).
DR SignaLink; P55017; -.
DR SIGNOR; P55017; -.
DR BioGRID-ORCS; 6559; 10 hits in 1075 CRISPR screens.
DR ChiTaRS; SLC12A3; human.
DR GeneWiki; Sodium-chloride_symporter; -.
DR GenomeRNAi; 6559; -.
DR Pharos; P55017; Tclin.
DR PRO; PR:P55017; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P55017; protein.
DR Bgee; ENSG00000070915; Expressed in adult mammalian kidney and 61 other tissues.
DR ExpressionAtlas; P55017; baseline and differential.
DR Genevisible; P55017; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0015081; F:sodium ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015378; F:sodium:chloride symporter activity; TAS:Reactome.
DR GO; GO:0008511; F:sodium:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central.
DR GO; GO:0071241; P:cellular response to inorganic substance; IEA:Ensembl.
DR GO; GO:0055064; P:chloride ion homeostasis; IBA:GO_Central.
DR GO; GO:1902476; P:chloride transmembrane transport; IBA:GO_Central.
DR GO; GO:0006811; P:ion transport; TAS:Reactome.
DR GO; GO:0055075; P:potassium ion homeostasis; IBA:GO_Central.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IEA:Ensembl.
DR GO; GO:1904044; P:response to aldosterone; IEA:Ensembl.
DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IEA:Ensembl.
DR GO; GO:0055078; P:sodium ion homeostasis; IBA:GO_Central.
DR GO; GO:0035725; P:sodium ion transmembrane transport; ISS:BHF-UCL.
DR GO; GO:0006814; P:sodium ion transport; ISS:UniProtKB.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR013612; AA_permease_N.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR002948; SLC12A3.
DR InterPro; IPR004842; SLC12A_fam.
DR PANTHER; PTHR11827; PTHR11827; 1.
DR PANTHER; PTHR11827:SF9; PTHR11827:SF9; 1.
DR Pfam; PF00324; AA_permease; 1.
DR Pfam; PF08403; AA_permease_N; 1.
DR Pfam; PF03522; SLC12; 2.
DR PRINTS; PR01230; NACLTRNSPORT.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Chloride; Disease variant;
KW Glycoprotein; Ion transport; Membrane; Phosphoprotein; Reference proteome;
KW Sodium; Sodium transport; Symport; Transmembrane; Transmembrane helix;
KW Transport; Ubl conjugation.
FT CHAIN 1..1021
FT /note="Solute carrier family 12 member 3"
FT /id="PRO_0000178026"
FT TOPO_DOM 1..135
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 136..156
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 159..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 180..218
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 219..239
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 262..282
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 283..286
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 287..307
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 340..360
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 361..377
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 378..398
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 453..473
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 474..511
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 512..532
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 535..555
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 556..577
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 578..598
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 661..681
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 682..1021
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT MOD_RES 43
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 49
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 50
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 55
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 60
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 73
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 91
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 124
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT MOD_RES 126
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P59158"
FT CARBOHYD 406
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 426
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 95
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_040100"
FT VAR_SEQ 807
FT /note="V -> GARPSVSGAL (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:8528245"
FT /id="VSP_036318"
FT VARIANT 60
FT /note="T -> M (in GTLMNS; dbSNP:rs371443644)"
FT /evidence="ECO:0000269|PubMed:15069170,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039475"
FT VARIANT 62
FT /note="D -> H (in GTLMNS; dbSNP:rs757490496)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075931"
FT VARIANT 62
FT /note="D -> N (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:8900229"
FT /id="VAR_039476"
FT VARIANT 68
FT /note="E -> K (in GTLMNS; dbSNP:rs763210286)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039477"
FT VARIANT 69
FT /note="H -> N (in GTLMNS; dbSNP:rs780502516)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039478"
FT VARIANT 83
FT /note="R -> Q (in GTLMNS; dbSNP:rs768527231)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075932"
FT VARIANT 83
FT /note="R -> W (in GTLMNS; dbSNP:rs201255508)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075933"
FT VARIANT 90
FT /note="H -> Y (in GTLMNS; dbSNP:rs1596883431)"
FT /evidence="ECO:0000269|PubMed:15687331"
FT /id="VAR_039479"
FT VARIANT 121
FT /note="E -> D (in GTLMNS; 27% residual Na(+) uptake
FT activity; increased MAPK1/3 (ERK1/2) phosphorylation in
FT response to IL18; no effect on localization at the plasma
FT membrane; dbSNP:rs146632606)"
FT /evidence="ECO:0000269|PubMed:22009145,
FT ECO:0000269|PubMed:26099046"
FT /id="VAR_075934"
FT VARIANT 135
FT /note="R -> C (in GTLMNS; dbSNP:rs749742102)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075935"
FT VARIANT 145
FT /note="R -> C (in GTLMNS; dbSNP:rs148945966)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075936"
FT VARIANT 145
FT /note="R -> H (in GTLMNS; dbSNP:rs374324018)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039480"
FT VARIANT 150
FT /note="I -> M (in GTLMNS; dbSNP:rs143714318)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075937"
FT VARIANT 153
FT /note="V -> M (in GTLMNS; dbSNP:rs779074538)"
FT /evidence="ECO:0000269|PubMed:17654016,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039481"
FT VARIANT 154
FT /note="I -> F (in GTLMNS; dbSNP:rs748547209)"
FT /evidence="ECO:0000269|PubMed:11168953"
FT /id="VAR_039482"
FT VARIANT 157
FT /note="L -> P (in GTLMNS; dbSNP:rs775047246)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075938"
FT VARIANT 158
FT /note="R -> L (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075939"
FT VARIANT 158
FT /note="R -> Q (in GTLMNS; dbSNP:rs1274973729)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039483"
FT VARIANT 163
FT /note="T -> M (in GTLMNS; dbSNP:rs267607050)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039484"
FT VARIANT 166
FT /note="A -> V (in GTLMNS; dbSNP:rs779683214)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075940"
FT VARIANT 172
FT /note="W -> R (in GTLMNS; dbSNP:rs757792232)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039485"
FT VARIANT 178
FT /note="S -> L (in GTLMNS; dbSNP:rs772589653)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039486"
FT VARIANT 180
FT /note="T -> K (in GTLMNS; dbSNP:rs146158333)"
FT /evidence="ECO:0000269|PubMed:10616841"
FT /id="VAR_039487"
FT VARIANT 186
FT /note="G -> D (in GTLMNS; dbSNP:rs759426055)"
FT /evidence="ECO:0000269|PubMed:8900229"
FT /id="VAR_039488"
FT VARIANT 192
FT /note="I -> T (in GTLMNS; associated with deletion of N-
FT 566; dbSNP:rs1231715433)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075941"
FT VARIANT 194
FT /note="T -> I (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075942"
FT VARIANT 209
FT /note="R -> Q (in GTLMNS; dbSNP:rs758035631)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039489"
FT VARIANT 209
FT /note="R -> W (in GTLMNS; dbSNP:rs28936388)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:8528245, ECO:0000269|PubMed:8900229,
FT ECO:0000269|PubMed:9734597"
FT /id="VAR_007113"
FT VARIANT 215
FT /note="L -> P (in GTLMNS; dbSNP:rs780594361)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039490"
FT VARIANT 226
FT /note="A -> T (in GTLMNS; dbSNP:rs774753202)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039491"
FT VARIANT 230
FT /note="G -> D (in GTLMNS; dbSNP:rs375990084)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039492"
FT VARIANT 235
FT /note="T -> R (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075943"
FT VARIANT 259
FT /note="D -> N (in GTLMNS; dbSNP:rs780461639)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075944"
FT VARIANT 261
FT /note="R -> H (in GTLMNS; dbSNP:rs914588619)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039493"
FT VARIANT 264
FT /note="A -> G (in dbSNP:rs1529927)"
FT /evidence="ECO:0000269|PubMed:11940055,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:17885550,
FT ECO:0000269|PubMed:8528245, ECO:0000269|PubMed:8812482"
FT /id="VAR_039494"
FT VARIANT 272
FT /note="L -> P (in GTLMNS; dbSNP:rs568513106)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075945"
FT VARIANT 283
FT /note="S -> Y (in GTLMNS; dbSNP:rs1380031877)"
FT /evidence="ECO:0000269|PubMed:15687331"
FT /id="VAR_039495"
FT VARIANT 284
FT /note="K -> R (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:11168953"
FT /id="VAR_039496"
FT VARIANT 304
FT /note="T -> M (in GTLMNS; dbSNP:rs755069436)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075946"
FT VARIANT 304
FT /note="T -> P (in GTLMNS; dbSNP:rs753840283)"
FT /evidence="ECO:0000269|PubMed:10988270,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039497"
FT VARIANT 313
FT /note="A -> V (in GTLMNS; dbSNP:rs140551719)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039498"
FT VARIANT 316
FT /note="G -> V (in GTLMNS; dbSNP:rs748920885)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039499"
FT VARIANT 321
FT /note="R -> W (in GTLMNS; dbSNP:rs150046661)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039500"
FT VARIANT 334
FT /note="R -> W (in GTLMNS; dbSNP:rs770702194)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039501"
FT VARIANT 342
FT /note="G -> A (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039502"
FT VARIANT 349
FT /note="P -> L (in GTLMNS; dbSNP:rs121909383)"
FT /evidence="ECO:0000269|PubMed:8528245,
FT ECO:0000269|PubMed:8900229"
FT /id="VAR_007114"
FT VARIANT 374
FT /note="G -> E (in GTLMNS; dbSNP:rs773669504)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075947"
FT VARIANT 374
FT /note="G -> V (in GTLMNS; dbSNP:rs773669504)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039503"
FT VARIANT 382
FT /note="T -> M (in GTLMNS; dbSNP:rs187885782)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075948"
FT VARIANT 392
FT /note="T -> I (in GTLMNS; complete loss Na(+) uptake
FT activity; partial loss of localization at the plasma
FT membrane; dbSNP:rs748575829)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075949"
FT VARIANT 399
FT /note="R -> C (in GTLMNS; dbSNP:rs775931992)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039504"
FT VARIANT 421
FT /note="C -> R (in GTLMNS; dbSNP:rs28936387)"
FT /evidence="ECO:0000269|PubMed:8528245"
FT /id="VAR_007115"
FT VARIANT 433..436
FT /note="QHSC -> L (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075950"
FT VARIANT 439
FT /note="G -> S (in GTLMNS; does not affect MAPK1/3 (ERK1/2)
FT phosphorylation in response to IL18; dbSNP:rs759377924)"
FT /evidence="ECO:0000269|PubMed:10988270,
FT ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:26099046,
FT ECO:0000269|PubMed:8900229"
FT /id="VAR_039505"
FT VARIANT 442
FT /note="N -> S (in GTLMNS; 68% residual Na(+) uptake
FT activity; partial loss of localization at the plasma
FT membrane)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075951"
FT VARIANT 463
FT /note="G -> E (in GTLMNS; dbSNP:rs1375515522)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039506"
FT VARIANT 463
FT /note="G -> R (in GTLMNS; dbSNP:rs374163823)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075952"
FT VARIANT 464
FT /note="A -> T (in GTLMNS; dbSNP:rs201945662)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039507"
FT VARIANT 475
FT /note="S -> C (in GTLMNS; 40% residual Na(+) uptake
FT activity; increased MAPK1/3 (ERK1/2) phosphorylation in
FT response to IL18; no effect on localization at the plasma
FT membrane; dbSNP:rs373017321)"
FT /evidence="ECO:0000269|PubMed:22009145,
FT ECO:0000269|PubMed:26099046"
FT /id="VAR_075953"
FT VARIANT 478
FT /note="K -> E (in GTLMNS; dbSNP:rs1355705043)"
FT /evidence="ECO:0000269|PubMed:8900229"
FT /id="VAR_039508"
FT VARIANT 486
FT /note="D -> N (in GTLMNS; dbSNP:rs753523115)"
FT /evidence="ECO:0000269|PubMed:8528245,
FT ECO:0000269|PubMed:8900229"
FT /id="VAR_007116"
FT VARIANT 489
FT /note="Y -> H (in GTLMNS; 48% residual Na(+) uptake
FT activity; no effect on localization at the plasma
FT membrane)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075954"
FT VARIANT 496
FT /note="G -> C (in GTLMNS; dbSNP:rs777612082)"
FT /evidence="ECO:0000269|PubMed:8528245,
FT ECO:0000269|PubMed:8900229"
FT /id="VAR_007117"
FT VARIANT 507
FT /note="R -> C (in GTLMNS; dbSNP:rs369510226)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075955"
FT VARIANT 523
FT /note="A -> T (in GTLMNS; dbSNP:rs781137708)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075956"
FT VARIANT 534
FT /note="N -> S (in GTLMNS; dbSNP:rs780433336)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075957"
FT VARIANT 536
FT /note="F -> L (in GTLMNS; dbSNP:rs748650798)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075958"
FT VARIANT 542
FT /note="L -> P (in GTLMNS; dbSNP:rs574357286)"
FT /evidence="ECO:0000269|PubMed:8900229"
FT /id="VAR_039509"
FT VARIANT 546
FT /note="S -> G (in GTLMNS; dbSNP:rs1451284628)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075959"
FT VARIANT 555
FT /note="S -> L (in GTLMNS; dbSNP:rs148038173)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039510"
FT VARIANT 560
FT /note="P -> H (in GTLMNS; dbSNP:rs1402444800)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039511"
FT VARIANT 560
FT /note="P -> R (in GTLMNS; dbSNP:rs1402444800)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075960"
FT VARIANT 561
FT /note="Missing (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:8528245"
FT /id="VAR_007118"
FT VARIANT 566
FT /note="Missing (in GTLMNS; associated with T-192)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075961"
FT VARIANT 569
FT /note="A -> E (in GTLMNS; dbSNP:rs79351185)"
FT /evidence="ECO:0000269|PubMed:10616841"
FT /id="VAR_039512"
FT VARIANT 569
FT /note="A -> V (in GTLMNS; dbSNP:rs79351185)"
FT /evidence="ECO:0000269|PubMed:15069170"
FT /id="VAR_039513"
FT VARIANT 578
FT /note="V -> M (in GTLMNS; dbSNP:rs139329616)"
FT /evidence="ECO:0000269|PubMed:10616841"
FT /id="VAR_039514"
FT VARIANT 588
FT /note="A -> V (in GTLMNS; dbSNP:rs121909382)"
FT /evidence="ECO:0000269|PubMed:8528245,
FT ECO:0000269|PubMed:8900229"
FT /id="VAR_007119"
FT VARIANT 613
FT /note="G -> S (in GTLMNS; dbSNP:rs1222807128)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039515"
FT VARIANT 615
FT /note="S -> L (in GTLMNS; dbSNP:rs779160677)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:12112667, ECO:0000269|PubMed:22009145"
FT /id="VAR_039516"
FT VARIANT 615
FT /note="S -> W (in GTLMNS; dbSNP:rs779160677)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039517"
FT VARIANT 623
FT /note="L -> P (in GTLMNS; dbSNP:rs121909385)"
FT /evidence="ECO:0000269|PubMed:12008755,
FT ECO:0000269|PubMed:8954067"
FT /id="VAR_039518"
FT VARIANT 630
FT /note="G -> V (in GTLMNS; dbSNP:rs121909384)"
FT /evidence="ECO:0000269|PubMed:8528245"
FT /id="VAR_007120"
FT VARIANT 642
FT /note="R -> C (in GTLMNS; dbSNP:rs200697179)"
FT /evidence="ECO:0000269|PubMed:10616841,
FT ECO:0000269|PubMed:15069170, ECO:0000269|PubMed:22009145"
FT /id="VAR_039519"
FT VARIANT 642
FT /note="R -> G (in GTLMNS; dbSNP:rs200697179)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:12112667, ECO:0000269|PubMed:22009145"
FT /id="VAR_039520"
FT VARIANT 642
FT /note="R -> H (in GTLMNS; dbSNP:rs147901432)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:9734597"
FT /id="VAR_039521"
FT VARIANT 643
FT /note="P -> L (in GTLMNS; dbSNP:rs140012781)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:11940055, ECO:0000269|PubMed:22009145"
FT /id="VAR_039522"
FT VARIANT 647
FT /note="V -> M (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075962"
FT VARIANT 649
FT /note="T -> R (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039523"
FT VARIANT 655
FT /note="R -> C (in GTLMNS; dbSNP:rs747249619)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039524"
FT VARIANT 655
FT /note="R -> H (in GTLMNS; dbSNP:rs121909380)"
FT /evidence="ECO:0000269|PubMed:22009145,
FT ECO:0000269|PubMed:8528245"
FT /id="VAR_007121"
FT VARIANT 655
FT /note="R -> L (in GTLMNS; dbSNP:rs121909380)"
FT /evidence="ECO:0000269|PubMed:8528245"
FT /id="VAR_007122"
FT VARIANT 672
FT /note="M -> I (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:16429844"
FT /id="VAR_039525"
FT VARIANT 677
FT /note="V -> L (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039526"
FT VARIANT 677
FT /note="V -> M (in GTLMNS; dbSNP:rs771326058)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039527"
FT VARIANT 713
FT /note="I -> IKAFYSDVI (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075963"
FT VARIANT 728
FT /note="A -> T (in dbSNP:rs36049418)"
FT /evidence="ECO:0000269|PubMed:17885550,
FT ECO:0000269|PubMed:8528245"
FT /id="VAR_007123"
FT VARIANT 729
FT /note="G -> V (in GTLMNS; dbSNP:rs373901523)"
FT /evidence="ECO:0000269|PubMed:11168953,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039528"
FT VARIANT 731
FT /note="G -> R (in GTLMNS; dbSNP:rs752101663)"
FT /evidence="ECO:0000269|PubMed:10988270,
FT ECO:0000269|PubMed:8900229"
FT /id="VAR_039529"
FT VARIANT 735
FT /note="P -> R (in GTLMNS; dbSNP:rs757761069)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075964"
FT VARIANT 738
FT /note="L -> R (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:9734597"
FT /id="VAR_039530"
FT VARIANT 741
FT /note="G -> R (in GTLMNS; dbSNP:rs138977195)"
FT /evidence="ECO:0000269|PubMed:10988270,
FT ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:8528245,
FT ECO:0000269|PubMed:9734597"
FT /id="VAR_007124"
FT VARIANT 751
FT /note="P -> L (in GTLMNS; 54% residual Na(+) uptake
FT activity; no effect on localization at the plasma membrane;
FT dbSNP:rs368068353)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075965"
FT VARIANT 824
FT /note="S -> T (in GTLMNS; dbSNP:rs146845953)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075966"
FT VARIANT 839
FT /note="D -> N (in GTLMNS; dbSNP:rs1298687889)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075967"
FT VARIANT 849
FT /note="L -> F (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075968"
FT VARIANT 849
FT /note="L -> H (in GTLMNS; dbSNP:rs185927948)"
FT /evidence="ECO:0000269|PubMed:10616841,
FT ECO:0000269|PubMed:15069170, ECO:0000269|PubMed:17873326"
FT /id="VAR_039531"
FT VARIANT 850
FT /note="L -> P (in GTLMNS; dbSNP:rs121909379)"
FT /evidence="ECO:0000269|PubMed:22009145,
FT ECO:0000269|PubMed:8528245, ECO:0000269|PubMed:9734597"
FT /id="VAR_007125"
FT VARIANT 852
FT /note="R -> C (in GTLMNS; dbSNP:rs373899077)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:9734597"
FT /id="VAR_039532"
FT VARIANT 852
FT /note="R -> H (in GTLMNS; dbSNP:rs751929135)"
FT /evidence="ECO:0000269|PubMed:17873326"
FT /id="VAR_039533"
FT VARIANT 852
FT /note="R -> S (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:12112667"
FT /id="VAR_039534"
FT VARIANT 854
FT /note="R -> K (in dbSNP:rs8060046)"
FT /id="VAR_060106"
FT VARIANT 862
FT /note="R -> C (in GTLMNS; dbSNP:rs754505583)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075969"
FT VARIANT 867
FT /note="G -> S (in GTLMNS; dbSNP:rs370301695)"
FT /evidence="ECO:0000269|PubMed:17654016"
FT /id="VAR_039535"
FT VARIANT 871
FT /note="R -> H (in GTLMNS)"
FT /evidence="ECO:0000269|PubMed:15687331"
FT /id="VAR_039536"
FT VARIANT 872
FT /note="M -> T (in GTLMNS; dbSNP:rs752124879)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075970"
FT VARIANT 887
FT /note="R -> Q (in GTLMNS; dbSNP:rs369360334)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075971"
FT VARIANT 904
FT /note="R -> Q (in dbSNP:rs11643718)"
FT /evidence="ECO:0000269|PubMed:10988270,
FT ECO:0000269|PubMed:12112667, ECO:0000269|PubMed:17885550,
FT ECO:0000269|PubMed:9734597"
FT /id="VAR_039537"
FT VARIANT 919
FT /note="R -> C (increases sodium transport;
FT dbSNP:rs12708965)"
FT /evidence="ECO:0000269|PubMed:17885550,
FT ECO:0000269|PubMed:9734597"
FT /id="VAR_039538"
FT VARIANT 934
FT /note="R -> W (in GTLMNS; dbSNP:rs201721269)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075972"
FT VARIANT 935
FT /note="R -> W (in GTLMNS; unknown pathological
FT significance; dbSNP:rs56125220)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075973"
FT VARIANT 955
FT /note="R -> Q (in GTLMNS; dbSNP:rs202114767)"
FT /evidence="ECO:0000269|PubMed:22009145,
FT ECO:0000269|PubMed:8528245"
FT /id="VAR_007126"
FT VARIANT 958
FT /note="R -> G (in GTLMNS; dbSNP:rs773428143)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039539"
FT VARIANT 980
FT /note="G -> R (in GTLMNS; dbSNP:rs34803727)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075974"
FT VARIANT 985
FT /note="C -> Y (in GTLMNS; dbSNP:rs199849117)"
FT /evidence="ECO:0000269|PubMed:12112667,
FT ECO:0000269|PubMed:22009145"
FT /id="VAR_039540"
FT VARIANT 1009
FT /note="R -> Q (in GTLMNS; dbSNP:rs370175770)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075975"
FT VARIANT 1021
FT /note="Q -> R (in GTLMNS; 58% residual Na(+) uptake
FT activity; decreased MAPK1/3 (ERK1/2) phosphorylation in
FT response to IL18; partial loss of localization at the
FT plasma membrane; dbSNP:rs762026283)"
FT /evidence="ECO:0000269|PubMed:22009145"
FT /id="VAR_075976"
FT CONFLICT 459..460
FT /note="AG -> VV (in Ref. 2; CAA62613)"
FT /evidence="ECO:0000305"
FT CONFLICT 539
FT /note="S -> P (in Ref. 3; AK315298)"
FT /evidence="ECO:0000305"
FT CONFLICT 766
FT /note="D -> E (in Ref. 1; AAC50355)"
FT /evidence="ECO:0000305"
FT CONFLICT 778
FT /note="Missing (in Ref. 3; AK315298)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1021 AA; 113139 MW; 629C5A42F3234B71 CRC64;
MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT
IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKQEGRHL HALAFDSRPS HEMTDGLVEG
EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI WGVILYLRLP WITAQAGIVL TWIIILLSVT
VTSITGLSIS AISTNGKVKS GGTYFLISRS LGPELGGSIG LIFAFANAVG VAMHTVGFAE
TVRDLLQEYG APIVDPINDI RIIAVVSVTV LLAISLAGME WESKAQVLFF LVIMVSFANY
LVGTLIPPSE DKASKGFFSY RADIFVQNLV PDWRGPDGTF FGMFSIFFPS ATGILAGANI
SGDLKDPAIA IPKGTLMAIF WTTISYLAIS ATIGSCVVRD ASGVLNDTVT PGWGACEGLA
CSYGWNFTEC TQQHSCHYGL INYYQTMSMV SGFAPLITAG IFGATLSSAL ACLVSAAKVF
QCLCEDQLYP LIGFFGKGYG KNKEPVRGYL LAYAIAVAFI IIAELNTIAP IISNFFLCSY
ALINFSCFHA SITNSPGWRP SFQYYNKWAA LFGAIISVVI MFLLTWWAAL IAIGVVLFLL
LYVIYKKPEV NWGSSVQAGS YNLALSYSVG LNEVEDHIKN YRPQCLVLTG PPNFRPALVD
FVGTFTRNLS LMICGHVLIG PHKQRMPELQ LIANGHTKWL NKRKIKAFYS DVIAEDLRRG
VQILMQAAGL GRMKPNILVV GFKKNWQSAH PATVEDYIGI LHDAFDFNYG VCVMRMREGL
NVSKMMQAHI NPVFDPAEDG KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG
GLTLLIPYLL GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLGF HEVHILPDIN
QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR VKSLRQVRLN
EIVLDYSRDA ALIVITLPIG RKGKCPSSLY MAWLETLSQD LRPPVILIRG NQENVLTFYC
Q
