NameSolute carrier family 12 member 3
Synonyms
  • Na-Cl cotransporter
  • Na-Cl symporter
  • NCC
  • Thiazide-sensitive sodium-chloride cotransporter
  • TSC
Gene NameSLC12A3
OrganismHuman
Amino acid sequence
>lcl|BSEQ0021968|Solute carrier family 12 member 3
MAELPTTETPGDATLCSGRFTISTLLSSDEPSPPAAYDSSHPSHLTHSSTFCMRTFGYNT
IDVVPTYEHYANSTQPGEPRKVRPTLADLHSFLKQEGRHLHALAFDSRPSHEMTDGLVEG
EAGTSSEKNPEEPVRFGWVKGVMIRCMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVT
VTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAE
TVRDLLQEYGAPIVDPINDIRIIAVVSVTVLLAISLAGMEWESKAQVLFFLVIMVSFANY
LVGTLIPPSEDKASKGFFSYRADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANI
SGDLKDPAIAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGVLNDTVTPGWGACEGLA
CSYGWNFTECTQQHSCHYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVF
QCLCEDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSY
ALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISVVIMFLLTWWAALIAIGVVLFLL
LYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVD
FVGTFTRNLSLMICGHVLIGPHKQRMPELQLIANGHTKWLNKRKIKAFYSDVIAEDLRRG
VQILMQAAGLGRMKPNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGL
NVSKMMQAHINPVFDPAEDGKEASARVDPKALVKEEQATTIFQSEQGKKTIDIYWLFDDG
GLTLLIPYLLGRKRRWSKCKIRVFVGGQINRMDQERKAIISLLSKFRLGFHEVHILPDIN
QNPRAEHTKRFEDMIAPFRLNDGFKDEATVNEMRRDCPWKISDEEITKNRVKSLRQVRLN
EIVLDYSRDAALIVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYC
Q
Number of residues1021
Molecular Weight113138.04
Theoretical pI7.94
GO Classification
Functions
  • sodium
  • potassium ion symporter activity
  • potassium
  • transporter activity
  • sodium ion transmembrane transporter activity
Processes
  • sodium ion transmembrane transport
  • transmembrane transport
  • cell volume homeostasis
  • chloride ion homeostasis
  • transport
  • chloride transmembrane transport
  • ion transport
  • potassium ion homeostasis
  • potassium ion import
  • sodium ion transport
  • sodium ion homeostasis
Components
  • cytosol
  • extracellular exosome
  • integral component of plasma membrane
  • apical plasma membrane
  • membrane
  • plasma membrane
General FunctionTransporter activity
Specific FunctionKey mediator of sodium and chloride reabsorption in this nephron segment, accounting for a significant fraction of renal sodium reabsorption.
Pfam Domain Function
Transmembrane Regions136-156 159-179 219-239 262-282 287-307 340-360 378-398 453-473 512-532 535-555 578-598 661-681
GenBank Protein ID1172161
UniProtKB IDP55017
UniProtKB Entry NameS12A3_HUMAN
Cellular LocationCell membrane
Gene sequence
>lcl|BSEQ0021969|Solute carrier family 12 member 3 (SLC12A3)
ATGGCAGAACTGCCCACAACAGAGACGCCTGGGGACGCCACTTTGTGCAGCGGGCGCTTC
ACCATCAGCACACTGCTGAGCAGTGATGAGCCCTCTCCACCAGCTGCCTATGACAGCAGC
CACCCCAGCCACCTGACCCACAGCAGCACCTTCTGCATGCGCACCTTTGGCTACAACACG
ATCGATGTGGTGCCCACATATGAGCACTATGCCAACAGCACCCAGCCTGGTGAGCCCCGG
AAGGTCCGGCCCACACTGGCTGACCTGCACTCCTTCCTCAAGCAGGAAGGCAGACACCTG
CATGCCCTGGCCTTTGACAGCCGGCCCAGCCACGAGATGACTGATGGGCTGGTGGAGGGC
GAGGCAGGCACCAGCAGCGAGAAGAACCCCGAGGAGCCAGTGCGCTTCGGCTGGGTCAAG
GGGGTGATGATTCGTTGCATGCTCAACATTTGGGGCGTGATCCTCTACCTGCGGCTGCCC
TGGATTACGGCCCAGGCAGGCATCGTCCTGACCTGGATCATCATCCTGCTGTCGGTCACG
GTGACCTCCATCACAGGCCTCTCCATCTCAGCCATCTCCACCAATGGCAAGGTCAAGTCA
GGTGGCACCTACTTCCTCATCTCCCGGAGTCTGGGCCCAGAGCTTGGGGGCTCCATCGGC
CTCATTTTCGCTTTCGCCAATGCCGTGGGTGTGGCCATGCACACGGTGGGCTTTGCAGAG
ACCGTGCGGGACCTGCTCCAGGAGTATGGGGCACCCATCGTGGACCCCATTAACGACATC
CGCATCATTGGCGTGGTCTCGGTCACTGTGCTGCTGGCCATCTCCCTGGCTGGCATGGAG
TGGGAGTCCAAGGCCCAGGTGCTGTTCTTCCTTGTCATCATGGTCTCCTTTGCCAACTAT
TTAGTGGGGACGCTGATCCCCCCATCTGAGGACAAGGCCTCCAAAGGCTTCTTCAGCTAC
CGGGCGGACATTTTTGTCCAGAACTTGGTGCCTGACTGGCGGGGTCCAGATGGCACCTTC
TTCGGAATGTTCTCCATCTTCTTCCCCTCGGCCACAGGCATCCTGGCAGGGGCCAACATA
TCTGGTGACCTCAAGGACCCTGCTATAGCCATCCCCAAGGGGACCCTCATGGCCATTTTC
TGGACGACCATTTCCTACCTGGCCATCTCAGCCACCATTGGCTCCTGCGTGGTGCGTGAT
GCCTCTGGGGTCCTGAATGACACAGTGACCCCTGGCTGGGGTGCCTGCGAGGGGCTGGCC
TGCAGCTATGGCTGGAACTTCACCGAGTGCACCCAGCAGCACAGCTGCCACTACGGCCTC
ATCAACTATTACCAGACCATGAGCATGGTGTCAGGCTTCGCGCCCCTGATCACGGCTGGC
ATCTTCGGGGCCACCCTCTCCTCTGCCCTGGCCTGCCTTGTCTCTGCTGCCAAAGTCTTC
CAGTGCCTTTGCGAGGACCAGCTGTACCCACTGATCGGCTTCTTCGGCAAAGGCTATGGC
AAGAACAAGGAGCCCGTGCGTGGCTACCTGCTGGCCTACGCCATCGCTGTGGCCTTCATC
ATCATCGCTGAGCTCAACACCATAGCCCCCATCATTTCCAACTTCTTCCTCTGCTCCTAT
GCCCTCATCAACTTCAGCTGCTTCCACGCCTCCATCACCAACTCGCCTGGGTGGAGACCT
TCATTCCAATACTACAACAAGTGGGCGGCGCTGTTTGGGGCTATCATCTCCGTGGTCATC
ATGTTCCTCCTCACCTGGTGGGCGGCCCTCATCGCCATTGGCGTGGTGCTCTTCCTCCTG
CTCTATGTCATCTACAAGAAGCCAGAGGTAAATTGGGGCTCCTCGGTACAGGCTGGCTCC
TACAACCTGGCCCTCAGCTACTCGGTGGGCCTCAATGAGGTGGAAGACCACATCAAGAAC
TACCGCCCCCAGTGCCTGGTGCTCACGGGGCCCCCCAACTTCCGCCCGGCCCTGGTGGAC
TTTGTGGGCACCTTCACCCGGAACCTCAGCCTGATGATCTGTGGCCACGTGCTCATCGGA
CCCCACAAGCAGAGGATGCCTGAGCTCCAGCTCATCGCCAACGGGCACACCAAGTGGCTG
AACAAGAGGAAGATCAAGGCCTTCTACTCGGATGTCATTGCCGAGGACCTCCGCAGAGGC
GTCCAGATCCTCATGCAGGCCGCAGGTCTCGGGAGAATGAAGCCCAACATTCTGGTGGTT
GGGTTCAAGAAGAACTGGCAGTCGGCTCACCCGGCCACAGTGGAAGACTACATTGGCATC
CTCCATGATGCCTTTGATTTCAACTATGGCGTGTGTGTCATGAGGATGCGGGAGGGACTC
AACGTGTCCAAGATGATGCAGGCGCACATTAACCCCGTGTTTGACCCAGCGGAGGACGGG
AAGGAAGCCAGCGCCAGAGGTGCCAGGCCATCAGTCTCTGGCGCTTTGGACCCCAAGGCC
CTGGTGAAGGAGGAGCAGGCCACCACCATCTTCCAGTCGGAGCAGGGCAAGAAGACCATA
GACATCTACTGGCTCTTTGACGATGGAGGCCTCACCCTCCTCATTCCCTATCTCCTTGGC
CGCAAGAGGAGGTGGAGCAAATGCAAGATCCGTGTGTTCGTAGGCGGCCAGATTAACAGG
ATGGACCAGGAGAGAAAGGCGATCATTTCTCTGCTGAGCAAGTTCCGACTGGGATTCCAT
GAAGTCCACATCCTCCCTGACATCAACCAGAACCCTCGGGCTGAGCACACCAAGAGGTTT
GAGGACATGATTGCACCCTTCCGTCTGAATGATGGCTTCAAGGATGAGGCCACTGTCAAC
GAGATGCGGCGGGACTGCCCCTGGAAGATCTCAGATGAGGAGATTACGAAGAACAGAGTC
AAGTCCCTTCGGCAGGTGAGGCTGAATGAGATTGTGCTGGATTACTCCCGAGACGCTGCT
CTCATCGTCATCACTTTGCCCATAGGGAGGAAGGGGAAGTGCCCCAGCTCGCTGTACATG
GCCTGGCTGGAGACCCTGTCCCAGGACCTCAGACCTCCAGTCATCCTGATCCGAGGAAAC
CAGGAAAACGTGCTCACCTTTTACTGCCAGTAA
GenBank Gene IDU44128
GeneCard IDNot Available
GenAtlas IDSLC12A3
HGNC IDHGNC:10912
Chromosome Location16
Locus16q13
References
  1. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP: Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996 Jan;12(1):24-30. 8528245
  2. Mastroianni N, De Fusco M, Zollo M, Arrigo G, Zuffardi O, Bettinelli A, Ballabio A, Casari G: Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Genomics. 1996 Aug 1;35(3):486-93. 8812482
  3. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  4. Martin J, Han C, Gordon LA, Terry A, Prabhakar S, She X, Xie G, Hellsten U, Chan YM, Altherr M, Couronne O, Aerts A, Bajorek E, Black S, Blumer H, Branscomb E, Brown NC, Bruno WJ, Buckingham JM, Callen DF, Campbell CS, Campbell ML, Campbell EW, Caoile C, Challacombe JF, Chasteen LA, Chertkov O, Chi HC, Christensen M, Clark LM, Cohn JD, Denys M, Detter JC, Dickson M, Dimitrijevic-Bussod M, Escobar J, Fawcett JJ, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Goodwin LA, Grady DL, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Hildebrand CE, Huang W, Israni S, Jett J, Jewett PB, Kadner K, Kimball H, Kobayashi A, Krawczyk MC, Leyba T, Longmire JL, Lopez F, Lou Y, Lowry S, Ludeman T, Manohar CF, Mark GA, McMurray KL, Meincke LJ, Morgan J, Moyzis RK, Mundt MO, Munk AC, Nandkeshwar RD, Pitluck S, Pollard M, Predki P, Parson-Quintana B, Ramirez L, Rash S, Retterer J, Ricke DO, Robinson DL, Rodriguez A, Salamov A, Saunders EH, Scott D, Shough T, Stallings RL, Stalvey M, Sutherland RD, Tapia R, Tesmer JG, Thayer N, Thompson LS, Tice H, Torney DC, Tran-Gyamfi M, Tsai M, Ulanovsky LE, Ustaszewska A, Vo N, White PS, Williams AL, Wills PL, Wu JR, Wu K, Yang J, Dejong P, Bruce D, Doggett NA, Deaven L, Schmutz J, Grimwood J, Richardson P, Rokhsar DS, Eichler EE, Gilna P, Lucas SM, Myers RM, Rubin EM, Pennacchio LA: The sequence and analysis of duplication-rich human chromosome 16. Nature. 2004 Dec 23;432(7020):988-94. 15616553
  5. Cruz-Rangel S, Melo Z, Vazquez N, Meade P, Bobadilla NA, Pasantes-Morales H, Gamba G, Mercado A: Similar effects of all WNK3 variants on SLC12 cotransporters. Am J Physiol Cell Physiol. 2011 Sep;301(3):C601-8. doi: 10.1152/ajpcell.00070.2011. Epub 2011 May 25. 21613606
  6. Mastroianni N, Bettinelli A, Bianchetti M, Colussi G, De Fusco M, Sereni F, Ballabio A, Casari G: Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome. Am J Hum Genet. 1996 Nov;59(5):1019-26. 8900229
  7. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X: KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218. 22406640
  8. Takeuchi K, Kure S, Kato T, Taniyama Y, Takahashi N, Ikeda Y, Abe T, Narisawa K, Muramatsu Y, Abe K: Association of a mutation in thiazide-sensitive Na-Cl cotransporter with familial Gitelman's syndrome. J Clin Endocrinol Metab. 1996 Dec;81(12):4496-9. 8954067
  9. Lemmink HH, Knoers NV, Karolyi L, van Dijk H, Niaudet P, Antignac C, Guay-Woodford LM, Goodyer PR, Carel JC, Hermes A, Seyberth HW, Monnens LA, van den Heuvel LP: Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int. 1998 Sep;54(3):720-30. 9734597
  10. Melander O, Orho-Melander M, Bengtsson K, Lindblad U, Rastam L, Groop L, Hulthen UL: Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000 Sep;36(3):389-94. 10988270
  11. Monkawa T, Kurihara I, Kobayashi K, Hayashi M, Saruta T: Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome. J Am Soc Nephrol. 2000 Jan;11(1):65-70. 10616841
  12. Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB: Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int. 2001 Feb;59(2):710-7. 11168953
  13. Pantanetti P, Arnaldi G, Balercia G, Mantero F, Giacchetti G: Severe hypomagnesaemia-induced hypocalcaemia in a patient with Gitelman's syndrome. Clin Endocrinol (Oxf). 2002 Mar;56(3):413-8. 11940055
  14. Tajima T, Kobayashi Y, Abe S, Takahashi M, Konno M, Nakae J, Okuhara K, Satoh K, Ishikawa T, Imai T, Fujieda K: Two novel mutations of thiazide-sensitive Na-Cl cotrans porter (TSC) gene in two sporadic Japanese patients with Gitelman syndrome. Endocr J. 2002 Feb;49(1):91-6. 12008755
  15. Syren ML, Tedeschi S, Cesareo L, Bellantuono R, Colussi G, Procaccio M, Ali A, Domenici R, Malberti F, Sprocati M, Sacco M, Miglietti N, Edefonti A, Sereni F, Casari G, Coviello DA, Bettinelli A: Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome. Hum Mutat. 2002 Jul;20(1):78. 12112667
  16. Maki N, Komatsuda A, Wakui H, Ohtani H, Kigawa A, Aiba N, Hamai K, Motegi M, Yamaguchi A, Imai H, Sawada K: Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant. 2004 Jul;19(7):1761-6. Epub 2004 Apr 6. 15069170
  17. Lin SH, Shiang JC, Huang CC, Yang SS, Hsu YJ, Cheng CJ: Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome. J Clin Endocrinol Metab. 2005 May;90(5):2500-7. Epub 2005 Feb 1. 15687331
  18. Terui K, Shoji M, Yamashiki J, Hirai Y, Ishiguro A, Tsutaya S, Kageyama K, Yasujima M, Suda T: A novel mutation of the thiazide-sensitive sodium chloride cotransporter gene in a Japanese family with Gitelman syndrome. Clin Nephrol. 2006 Jan;65(1):57-60. 16429844
  19. Fava C, Montagnana M, Rosberg L, Burri P, Jonsson A, Wanby P, Wahrenberg H, Hulthen UL, Aurell M, Guidi GC, Melander O: Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes. DNA Seq. 2007 Oct;18(5):395-9. 17654016
  20. Aoi N, Nakayama T, Tahira Y, Haketa A, Yabuki M, Sekiyama T, Nakane C, Mano H, Kawachi H, Sato N, Soma M, Matsumoto K: Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome. Endocrine. 2007 Apr;31(2):149-53. 17873326
  21. Keszei AP, Tisler A, Backx PH, Andrulis IL, Bull SB, Logan AG: Molecular variants of the thiazide-sensitive Na+-Cl- cotransporter in hypertensive families. J Hypertens. 2007 Oct;25(10):2074-81. 17885550