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Gene Review

SLC12A3  -  solute carrier family 12 (sodium/chloride...

Homo sapiens

Synonyms: NCC, NCCT, Na-Cl cotransporter, Na-Cl symporter, Solute carrier family 12 member 3, ...
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Disease relevance of SLC12A3

  • We genotyped 11 common single nucleotide polymorphisms (SNPs) in the SLC12A3 gene in 177 patients with ESRD due to type 2 diabetes and 184 patients with diabetic retinopathy but with no signs of renal involvement [1].
  • In contrast, NCCT patients had hypocalciuria, hypomagnesemia, and marked hypokalemia [2].
  • We examined the genetic involvement of the TSC gene in essential hypertension in Japanese. DESIGN: Participants were recruited from outpatients of Osaka University Hospital. We investigated 386 hypertensive and 371 normotensive subjects [3].
  • Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome [4].
  • BACKGROUND: To investigate the genetic cause of inherited hypokalemic metabolic alkalosis associated with Gitelman's syndrome, we searched for mutations in the SLC12A3 gene (thiazide-sensitive NaCl cotransporter) among a set of patients from the Czech Republic and Slovakia [5].

High impact information on SLC12A3

  • Our survey of more than 1,200 SNPs indicates that more than 80% of TSC and Washington University candidate SNPs are polymorphic and that approximately 50% of the candidate SNPs from these two sources are common SNPs (with minor allele frequency of > or =20%) in any given population [6].
  • Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter ((22)Na-influx reduced 50%, P < 1 x 10(-9), surface expression reduced 75%, P < 1 x 10(-14) in the presence of WNK4) [7].
  • PHAII-causing missense mutations, which are remote from the kinase domain, also prevent inhibition of NCCT activity, providing insight into the pathophysiology of the disorder [7].
  • To address this possibility, we measured NCCT-mediated Na(+) influx and membrane expression in the presence of wild-type and mutant WNK4 by heterologous expression in Xenopus oocytes [7].
  • The Cl(-) dependence of PHAII phenotypes, their sensitivity to thiazide diuretics, and the observation that they constitute a "mirror image" of the phenotypes resulting from loss of function mutations in the thiazide-sensitive Na-Cl cotransporter (NCCT) suggest that PHAII may result from increased NCCT activity due to altered WNK signaling [7].

Chemical compound and disease context of SLC12A3

  • In a multicenter, double-blind, randomized, controlled trial, TSC 30% was compared with unfractionated heparin 5000 U/ml for prevention of catheter-related infections, thrombosis, and bleeding complications [8].
  • BACKGROUND: The combination of isosulfan blue (Lymphazurin) 1% and 99(m)Tc sulfur colloid (TSC) may improve the feasibility and accuracy of lymphatic mapping for colorectal cancer [9].

Biological context of SLC12A3


Anatomical context of SLC12A3

  • OBJECTIVE: The thiazide-sensitive Na-Cl cotransporter (TSC) is located in the distal renal tubules [3].
  • In this study, extensive mutational analyses of SLC12A3 were performed in 27 patients with GS, including genomic DNA sequencing, multiplex ligation-dependent probe amplification, cDNA analysis, and quantification of allele-specific transcripts, in parallel with functional analyses in Xenopus laevis oocytes and detailed phenotyping [15].
  • This promoter, and all other promoter constructs from SLC12A3, displayed repressor activity in CHO cells [16].
  • Protein-DNA interactions between the 182 bp region immediately upstream of the start codon and the nuclear proteins from rat kidney cortex and HeLa cells were examined to further clarify the role of the putative binding sites for SLC12A3 expression [16].
  • We sequenced 1959 bp of the 5' flanking region of human SLC12A3, located the area of transcription initiation, and used deletion constructs of the flanking region to determine areas that affect reporter gene expression in two cell lines, MDCT and CHO [16].

Associations of SLC12A3 with chemical compounds

  • Polymorphism of the solute carrier family 12 (sodium/chloride transporters) member 3, SLC12A3, gene at exon 23 (+78G/A: Arg913Gln) is associated with elevation of urinary albumin excretion in Japanese patients with type 2 diabetes: a 10-year longitudinal study [11].
  • The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule [12].
  • RESULTS: All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene [12].
  • Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3) [17].
  • The homology of the hTSC with rat TSC (rTSC) and rat bumetanide-sensitive sodium-potassium-chloride cotransporter (rBSC) was 86% and 64%, respectively, at the nucleotide level, and 92% and 61%, respectively, at the amino acid level [18].

Regulatory relationships of SLC12A3

  • Recent studies have revealed that cell surface expression of TSC is regulated by WNK1 and WNK4 [19].

Other interactions of SLC12A3


Analytical, diagnostic and therapeutic context of SLC12A3


  1. SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Kim, J.H., Shin, H.D., Park, B.L., Moon, M.K., Cho, Y.M., Hwang, Y.H., Oh, K.W., Kim, S.Y., Lee, H.K., Ahn, C., Park, K.S. Diabetes (2006) [Pubmed]
  2. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Peters, M., Jeck, N., Reinalter, S., Leonhardt, A., Tönshoff, B., Klaus G, G., Konrad, M., Seyberth, H.W. Am. J. Med. (2002) [Pubmed]
  3. G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women. Matsuo, A., Katsuya, T., Ishikawa, K., Sugimoto, K., Iwashima, Y., Yamamoto, K., Ohishi, M., Rakugi, H., Ogihara, T. J. Hypertens. (2004) [Pubmed]
  4. Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome. Bettinelli, A., Borsa, N., Syrén, M.L., Mattiello, C., Coviello, D., Edefonti, A., Giani, M., Travi, M., Tedeschi, S. Pediatr. Res. (2005) [Pubmed]
  5. Genetic analysis of Gitelman syndrome patients from the Czech Republic and Slovakia--three novel mutations found. Urbanová, M., Reiterová, J., Rysavá, R., Stekrová, J., Merta, M. Kidney Blood Press. Res. (2006) [Pubmed]
  6. Single-nucleotide polymorphisms in the public domain: how useful are they? Marth, G., Yeh, R., Minton, M., Donaldson, R., Li, Q., Duan, S., Davenport, R., Miller, R.D., Kwok, P.Y. Nat. Genet. (2001) [Pubmed]
  7. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Wilson, F.H., Kahle, K.T., Sabath, E., Lalioti, M.D., Rapson, A.K., Hoover, R.S., Hebert, S.C., Gamba, G., Lifton, R.P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Randomized, clinical trial comparison of trisodium citrate 30% and heparin as catheter-locking solution in hemodialysis patients. Weijmer, M.C., van den Dorpel, M.A., Van de Ven, P.J., ter Wee, P.M., van Geelen, J.A., Groeneveld, J.O., van Jaarsveld, B.C., Koopmans, M.G., le Poole, C.Y., Schrander-Van der Meer, A.M., Siegert, C.E., Stas, K.J. J. Am. Soc. Nephrol. (2005) [Pubmed]
  9. Lymphazurin 1% versus 99mTc sulfur colloid for lymphatic mapping in colorectal tumors: a comparative analysis. Saha, S., Dan, A.G., Berman, B., Wiese, D., Schochet, E., Barber, K., Choudhri, S., Kaushal, S., Ganatra, B., Desai, D., Nagaraju, M., Mannam, S. Ann. Surg. Oncol. (2004) [Pubmed]
  10. A single nucleotide polymorphism alters the activity of the renal Na+:Cl- cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity. Moreno, E., Tovar-Palacio, C., de los Heros, P., Guzmán, B., Bobadilla, N.A., Vázquez, N., Riccardi, D., Poch, E., Gamba, G. J. Biol. Chem. (2004) [Pubmed]
  11. Polymorphism of the solute carrier family 12 (sodium/chloride transporters) member 3, SLC12A3, gene at exon 23 (+78G/A: Arg913Gln) is associated with elevation of urinary albumin excretion in Japanese patients with type 2 diabetes: a 10-year longitudinal study. Nishiyama, K., Tanaka, Y., Nakajima, K., Mokubo, A., Atsumi, Y., Matsuoka, K., Watada, H., Hirose, T., Nomiyama, T., Maeda, S., Kawamori, R. Diabetologia (2005) [Pubmed]
  12. A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Coto, E., Rodriguez, J., Jeck, N., Alvarez, V., Stone, R., Loris, C., Rodriguez, L.M., Fischbach, M., Seyberth, H.W., Santos, F. Kidney Int. (2004) [Pubmed]
  13. The Na-(K)-Cl cotransporter family in the mammalian kidney: molecular identification and function(s). Delpire, E., Kaplan, M.R., Plotkin, M.D., Hebert, S.C. Nephrol. Dial. Transplant. (1996) [Pubmed]
  14. Gitelman syndrome: genetic and expression analysis of the thiazide-sensitive sodium-chloride transporter in blood cells. Riancho, J.A., Saro, G., Sañudo, C., Izquierdo, M.J., Zarrabeitia, M.T. Nephrol. Dial. Transplant. (2006) [Pubmed]
  15. Transcriptional and Functional Analyses of SLC12A3 Mutations: New Clues for the Pathogenesis of Gitelman Syndrome. Riveira-Munoz, E., Chang, Q., Godefroid, N., Hoenderop, J.G., Bindels, R.J., Dahan, K., Devuyst, O. J. Am. Soc. Nephrol. (2007) [Pubmed]
  16. Sequencing and characterization of the human thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene promoter. MacKenzie, S., Vaitkevicius, H., Lockette, W. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  17. Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Mastroianni, N., De Fusco, M., Zollo, M., Arrigo, G., Zuffardi, O., Bettinelli, A., Ballabio, A., Casari, G. Genomics (1996) [Pubmed]
  18. Identification of a cDNA encoding a thiazide-sensitive sodium-chloride cotransporter from the human and its mRNA expression in various tissues. Chang, H., Tashiro, K., Hirai, M., Ikeda, K., Kurokawa, K., Fujita, T. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  19. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. Kokubo, Y., Kamide, K., Inamoto, N., Tanaka, C., Banno, M., Takiuchi, S., Kawano, Y., Tomoike, H., Miyata, T. J. Hum. Genet. (2004) [Pubmed]
  20. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Hebert, S.C., Mount, D.B., Gamba, G. Pflugers Arch. (2004) [Pubmed]
  21. Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss. Meij, I.C., van den Heuvel, L.P., Hemmes, S., van der Vliet, W.A., Willems, J.L., Monnens, L.A., Knoers, N.V. Nephrol. Dial. Transplant. (2003) [Pubmed]
  22. A serum potassium level above 10 mmol/l in a patient predisposed to hypokalemia. Phillips, D.R., Ahmad, K.I., Waller, S.J., Meisner, P., Karet, F.E. Nature clinical practice. Nephrology. (2006) [Pubmed]
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