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Identification
HMDB Protein ID HMDBP03099
Secondary Accession Numbers
  • 8636
  • HMDBP06849
Name Solute carrier family 12 member 3
Synonyms
  1. Na-Cl symporter
  2. Thiazide-sensitive sodium-chloride cotransporter
Gene Name SLC12A3
Protein Type Unknown
Biological Properties
General Function Involved in transport
Specific Function Electrically silent transporter system. Mediates sodium and chloride reabsorption
Pathways
  • Amiloride Action Pathway
  • Bendroflumethiazide Action Pathway
  • Blue diaper syndrome
  • Bumetanide Action Pathway
  • Chlorothiazide Action Pathway
  • Chlorthalidone Action Pathway
  • Cyclothiazide Action Pathway
  • Cystinuria
  • Eplerenone Action Pathway
  • Ethacrynic Acid Action Pathway
  • Furosemide Action Pathway
  • Glucose Transporter Defect (SGLT2)
  • Hartnup Disorder
  • Hydrochlorothiazide Action Pathway
  • Hydroflumethiazide Action Pathway
  • Iminoglycinuria
  • Indapamide Action Pathway
  • Kidney Function
  • Lysinuric Protein Intolerance
  • Lysinuric protein intolerance (LPI)
  • Methyclothiazide Action Pathway
  • Metolazone Action Pathway
  • Polythiazide Action Pathway
  • Quinethazone Action Pathway
  • Spironolactone Action Pathway
  • Torsemide Action Pathway
  • Triamterene Action Pathway
  • Trichlormethiazide Action Pathway
Reactions Not Available
GO Classification
Component
membrane
cell part
membrane part
intrinsic to membrane
integral to membrane
Function
transmembrane transporter activity
substrate-specific transmembrane transporter activity
ion transmembrane transporter activity
transporter activity
anion transmembrane transporter activity
anion:cation symporter activity
cation:chloride symporter activity
Process
sodium ion transport
establishment of localization
transport
chloride transport
transmembrane transport
anion transport
inorganic anion transport
monovalent inorganic cation transport
ion transport
cation transport
Cellular Location
  1. Membrane
  2. Multi-pass membrane protein
Gene Properties
Chromosome Location Chromosome:1
Locus 16q13
SNPs SLC12A3
Gene Sequence
>3066 bp
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
AAGGAAGCCAGCGCCAGAGTGGACCCCAAGGCCCTGGTGAAGGAGGAGCAGGCCACCACC
ATCTTCCAGTCGGAGCAGGGCAAGAAGACCATAGACATCTACTGGCTCTTTGACGATGGA
GGCCTCACCCTCCTCATTCCCTATCTCCTTGGCCGCAAGAGGAGGTGGAGCAAATGCAAG
ATCCGTGTGTTCGTAGGCGGCCAGATTAACAGGATGGACCAGGAGAGAAAGGCGATCATT
TCTCTGCTGAGCAAGTTCCGACTGGGATTCCATGAAGTCCACATCCTCCCTGACATCAAC
CAGAACCCTCGGGCTGAGCACACCAAGAGGTTTGAGGACATGATTGCACCCTTCCGTCTG
AATGATGGCTTCAAGGATGAGGCCACTGTCAACGAGATGCGGCGGGACTGCCCCTGGAAG
ATCTCAGATGAGGAGATTACGAAGAACAGAGTCAAGTCCCTTCGGCAGGTGAGGCTGAAT
GAGATTGTGCTGGATTACTCCCGAGACGCTGCTCTCATCGTCATCACTTTGCCCATAGGG
AGGAAGGGGAAGTGCCCCAGCTCGCTGTACATGGCCTGGCTGGAGACCCTGTCCCAGGAC
CTCAGACCTCCAGTCATCCTGATCCGAGGAAACCAGGAAAACGTGCTCACCTTTTACTGC
CAGTAA
Protein Properties
Number of Residues 1021
Molecular Weight 113124.0
Theoretical pI 7.94
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • 136-156
  • 159-179
  • 219-239
  • 262-282
  • 287-307
  • 340-360
  • 378-398
  • 453-473
  • 512-532
  • 535-555
  • 578-598
  • 661-681
Protein Sequence
>Solute carrier family 12 member 3
MAELPTTETPGDATLCSGRFTISTLLSSDEPSPPAAYDSSHPSHLTHSSTFCMRTFGYNT
IDVVPTYEHYANSTQPGEPRKVRPTLADLHSFLKQEGRHLHALAFDSRPSHEMTDGLVEG
EAGTSSEKNPEEPVRFGWVKGVMIRCMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVT
VTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAE
TVRDLLQEYGAPIVDPINDIRIIGVVSVTVLLAISLAGMEWESKAQVLFFLVIMVSFANY
LVGTLIPPSEDKASKGFFSYRADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANI
SGDLKDPAIAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGVLNDTVTPGWGACEGLA
CSYGWNFTECTQQHSCHYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVF
QCLCEDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSY
ALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISVVIMFLLTWWAALIAIGVVLFLL
LYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVD
FVGTFTRNLSLMICGHVLIGPHKQRMPELQLIANGHTKWLNKRKIKAFYSDVIAEDLRRG
VQILMQAAGLGRMKPNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGL
NVSKMMQAHINPVFDPAEDGKEASARVDPKALVKEEQATTIFQSEQGKKTIDIYWLFDDG
GLTLLIPYLLGRKRRWSKCKIRVFVGGQINRMDQERKAIISLLSKFRLGFHEVHILPDIN
QNPRAEHTKRFEDMIAPFRLNDGFKDEATVNEMRRDCPWKISDEEITKNRVKSLRQVRLN
EIVLDYSRDAALIVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYC
Q
GenBank ID Protein 186910319
UniProtKB/Swiss-Prot ID P55017
UniProtKB/Swiss-Prot Entry Name S12A3_HUMAN
PDB IDs Not Available
GenBank Gene ID NM_001126108.1
GeneCard ID SLC12A3
GenAtlas ID SLC12A3
HGNC ID HGNC:10912
References
General References
  1. 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. [PubMed:15616553 ]
  2. 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. [PubMed:8528245 ]
  3. 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. [PubMed:8812482 ]
  4. 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. [PubMed:8900229 ]
  5. 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. [PubMed:8954067 ]
  6. 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. [PubMed:9734597 ]
  7. 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. [PubMed:10988270 ]
  8. 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. [PubMed:10616841 ]
  9. 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. [PubMed:11168953 ]
  10. 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. [PubMed:11940055 ]
  11. 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. [PubMed:12008755 ]
  12. 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. [PubMed:12112667 ]
  13. 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. [PubMed:15069170 ]
  14. 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. [PubMed:15687331 ]
  15. 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. [PubMed:16429844 ]
  16. 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. [PubMed:17654016 ]
  17. 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. [PubMed:17873326 ]
  18. 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. [PubMed:17885550 ]