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Gene Review

SLC12A6  -  solute carrier family 12...

Homo sapiens

Synonyms: ACCPN, Electroneutral potassium-chloride cotransporter 3, K-Cl cotransporter 3, KCC3, KCC3A, ...
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Disease relevance of SLC12A6


Psychiatry related information on SLC12A6


High impact information on SLC12A6

  • ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q [5].
  • The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum [5].
  • The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional [5].
  • KCC3 was expressed in many, but not all cells of the inner ear K(+) recycling pathway [6].
  • These data indicate that KCC3 is an important KCC isoform that may be involved in cell proliferation [7].

Biological context of SLC12A6


Anatomical context of SLC12A6

  • The expression of mouse KCC3 in Xenopus laevis oocytes reveals the expected functional characteristics of a K+Cl- cotransporter: Cl--dependent uptake of 86Rb+ which is strongly activated by cell swelling and weakly sensitive to furosemide [8].
  • KCC3 is predominantly expressed in kidney, heart, and brain, and is also expressed in skeletal muscle, placenta, lung, liver, and pancreas [11].
  • KCC3, initially cloned from vascular endothelial cells, is widely but not universally distributed and has an unknown physiological significance [7].
  • Here we show a tight link between the expression and activity of KCC3 and cell growth by a NIH/3T3 fibroblast expression system [7].
  • The KCC3 mRNA was highly expressed in brain, heart, skeletal muscle, and kidney, showing a distinct pattern and size from KCC1 and KCC2 [9].

Associations of SLC12A6 with chemical compounds

  • KCC3 transiently expressed in human embryonic kidney (HEK)-293 cells fulfilled three criteria for increased expression of K-Cl cotransport: stimulation of cotransport by swelling, treatment with N-ethylmaleimide, or treatment with staurosporine [11].
  • Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy [12].
  • Stable overexpression of KCC3 cDNA in HEK293 cells produced a glycoprotein of approximately 150 kDa, which was reduced to 120 kDa by glycosidase digestion [9].
  • NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter [13].
  • One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity [12].

Other interactions of SLC12A6

  • Although widely expressed, KCC3 transcripts are the most abundant in heart and kidney, and KCC4 is expressed in muscle, brain, lung, heart, and kidney [8].
  • KCC3 shares 75-76% identity at the amino acid level with human, pig, rat, and rabbit KCC1 and 67% identity with rat KCC2 [11].
  • The KCC3 mRNA level in endothelial cells increased on treatment with VEGF and decreased with the proinflammatory cytokine tumor necrosis factor alpha, whereas KCC1 mRNA levels remained unchanged [9].
  • A few reports indicate that the NO/cGMP/PKG signaling pathway regulates KCC1 and KCC3 mRNA expression in VSMCs at the post-transcriptional level [14].
  • Through the use of haplotype analysis we have confirmed the presence of a founder haplotype in the FC population, and identified critical recombinants which reduce the ACCPN candidate interval to a approximately 2 cM or 1000 Kb region flanked by markers D15S1040 and ACTC [15].

Analytical, diagnostic and therapeutic context of SLC12A6


  1. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Hebert, S.C., Mount, D.B., Gamba, G. Pflugers Arch. (2004) [Pubmed]
  2. Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder. Meyer, J., Johannssen, K., Freitag, C.M., Schraut, K., Teuber, I., Hahner, A., Mainhardt, C., Mössner, R., Volz, H.P., Wienker, T.F., McKeane, D., Stephan, D.A., Rouleau, G., Reif, A., Lesch, K.P. Int. J. Neuropsychopharmacol. (2005) [Pubmed]
  3. IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness. Hsu, Y.M., Chou, C.Y., Chen, H.H., Lee, W.Y., Chen, Y.F., Lin, P.W., Alper, S.L., Ellory, J.C., Shen, M.R. J. Cell. Physiol. (2007) [Pubmed]
  4. The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Casaubon, L.K., Melanson, M., Lopes-Cendes, I., Marineau, C., Andermann, E., Andermann, F., Weissenbach, J., Prévost, C., Bouchard, J.P., Mathieu, J., Rouleau, G.A. Am. J. Hum. Genet. (1996) [Pubmed]
  5. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Howard, H.C., Mount, D.B., Rochefort, D., Byun, N., Dupré, N., Lu, J., Fan, X., Song, L., Rivière, J.B., Prévost, C., Horst, J., Simonati, A., Lemcke, B., Welch, R., England, R., Zhan, F.Q., Mercado, A., Siesser, W.B., George, A.L., McDonald, M.P., Bouchard, J.P., Mathieu, J., Delpire, E., Rouleau, G.A. Nat. Genet. (2002) [Pubmed]
  6. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. Boettger, T., Rust, M.B., Maier, H., Seidenbecher, T., Schweizer, M., Keating, D.J., Faulhaber, J., Ehmke, H., Pfeffer, C., Scheel, O., Lemcke, B., Horst, J., Leuwer, R., Pape, H.C., Völkl, H., Hübner, C.A., Jentsch, T.J. EMBO J. (2003) [Pubmed]
  7. The KCl cotransporter isoform KCC3 can play an important role in cell growth regulation. Shen, M.R., Chou, C.Y., Hsu, K.F., Liu, H.S., Dunham, P.B., Holtzman, E.J., Ellory, J.C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. Mount, D.B., Mercado, A., Song, L., Xu, J., George, A.L., Delpire, E., Gamba, G. J. Biol. Chem. (1999) [Pubmed]
  9. Cloning, characterization, and chromosomal location of a novel human K+-Cl- cotransporter. Hiki, K., D'Andrea, R.J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G.R., Vadas, M.A., Gamble, J.R. J. Biol. Chem. (1999) [Pubmed]
  10. Chloride transport in the kidney: lessons from human disease and knockout mice. Jentsch, T.J. J. Am. Soc. Nephrol. (2005) [Pubmed]
  11. Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Race, J.E., Makhlouf, F.N., Logue, P.J., Wilson, F.H., Dunham, P.B., Holtzman, E.J. Am. J. Physiol. (1999) [Pubmed]
  12. Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy. Steinlein, O.K., Neubauer, B.A., Sander, T., Song, L., Stoodt, J., Mount, D.B. Epilepsy Res. (2001) [Pubmed]
  13. NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. Mercado, A., Vázquez, N., Song, L., Cortés, R., Enck, A.H., Welch, R., Delpire, E., Gamba, G., Mount, D.B. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  14. Regulation of K-Cl cotransport: from function to genes. Adragna, N.C., Fulvio, M.D., Lauf, P.K. J. Membr. Biol. (2004) [Pubmed]
  15. Fine mapping the candidate region for peripheral neuropathy with or without agenesis of the corpus callosum in the French Canadian population. Howard, H.C., Dubé, M.P., Prévost, C., Bouchard, J.P., Mathieu, J., Rouleau, G.A. Eur. J. Hum. Genet. (2002) [Pubmed]
  16. Volume-sensitive KCI cotransport associated with human cervical carcinogenesis. Shen, M.R., Chou, C.Y., Ellory, J.C. Pflugers Arch. (2000) [Pubmed]
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