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Gene Review

SLC26A3  -  solute carrier family 26 (anion exchanger)...

Homo sapiens

Synonyms: CLD, Chloride anion exchanger, DRA, Down-regulated in adenoma, Protein DRA, ...
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Disease relevance of SLC26A3

  • Of nine known human genes in this family, three (SLC26A2, SLC26A3 and SLC26A4) are associated with different human hereditary diseases [1].
  • Although the expression of the SLC26A3 mRNA was significantly decreased in severe ulcerative colitis (P < 0.05), the SLC26A3 protein levels remained unchanged in all groups [2].
  • Thus, pharmacological modulation of DRA might be a useful adjunct treatment of cystic fibrosis [3].
  • Mutations in the SLC26A3 (DRA (down-regulated in adenoma)) gene constitute the molecular etiology of congenital chloride-losing diarrhea in humans [4].
  • In intestinal tumors, the expression pattern of CLD was dependent on the differentiation status of the tissue studied: epithelial polyps with no or minor dysplasia showed abundant expression, whereas adenocarcinomas were negative [5].

Psychiatry related information on SLC26A3

  • Mutations in the DRA X box that disrupt the binding of this factor result in a lower level of gene expression, as does the presence of Id (a trans-dominant regulatory protein that negatively regulates helix-loop-helix proteins) [6].
  • Minimum standards for the description of participants in learning disabilities research. CLD Research Committee [7].

High impact information on SLC26A3

  • The CLD locus was previously mapped to 7q3 adjacent to the cystic fibrosis gene (CFTR) [8].
  • Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea [8].
  • We conclude that DRA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated [8].
  • In this study, we report segregation of two missense mutations, delta V317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients [8].
  • In addition, presentation of endocytosed antigen to HLA-DR-restricted T cells is defective in the mutant, but can be restored by transfection of a wild type DRA gene [9].

Chemical compound and disease context of SLC26A3

  • The protein product of the DRA gene, a gene whose expression is down-regulated in colon adenomas and adenocarcinomas, is a membrane glycoprotein and a member of a family of sulfate transporters [10].
  • The down-regulated in adenoma (DRA) gene encodes an intestine-specific membrane glycoprotein [10].
  • Study patients had a birth weight < 1000 g and were about 28 d old when they were classified as normal control subjects (n = 8) or as having CLD (n = 26, abnormal chest X-ray, supplemental O2 requirement +/- ventilator) [11].
  • We compared the postnatal changes (days 1-28) in red blood cell glutathione and plasma sulfhydryl content in preterm babies developing chronic lung disease (CLD, n = 13) to those in babies with respiratory distress syndrome (RDS, n = 13) and control babies (n = 21) [12].
  • Whole blood manganese concentrations also were measured in patients with chronic liver disease (CLD, n = 10) and control subjects (n = 10) [13].

Biological context of SLC26A3


Anatomical context of SLC26A3

  • Two CLD missense disease mutants of hDRA were nonfunctional in oocytes [3].
  • DRA (down regulated in adenoma, SLC26A3) is an anion exchanger that mediates electroneutral NaCl absorption in the ileum and proximal colon together with NHE3 (Na/H exchanger isoform 3), and that is involved in duodenal and possibly pancreatic bicarbonate secretion [17].
  • Using an overlay assay with the recombinant DRA C-terminus as a ligand, a 70 kDa protein was labeled, which was restricted to the brush border membrane in rabbit duodenal and ileal mucosa and was not detected in the colon [18].
  • The CFTR associated protein CAP70 interacts with the apical Cl-/HCO3- exchanger DRA in rabbit small intestinal mucosa [18].
  • In inflammatory bowel disease and ischemic colitis, expression of CLD mRNA in colon epithelium was similar to histologically normal colon epithelium, but the protein was found deeper in crypts, including proliferative epithelial cells [5].

Associations of SLC26A3 with chemical compounds

  • At least three of the SLC26 exchangers mediate electrogenic Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchange; the stoichiometry of Cl(-)-HCO(3)(-) exchange appears to differ between SLC26 paralogs, such that SLC26A3 transports >/=2 Cl(-) ions per HCO(3)(-) ion, whereas SLC26A6 transports >/=2 HCO(3)(-) ions per Cl(-) ion [19].
  • Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea [14].
  • The expression of the closely related anion transporter diastrophic dysplasia sulfate transporter, DTDST, was also examined and compared with that of CLD in colon [5].
  • SLC26 anion exchangers (probably SLC26A3 and SLC26A6) are expressed on the apical membrane of pancreatic duct cells and play a key role in HCO3- secretion; a process that is inhibited by the neuropeptide, substance P (SP) [20].
  • The predicted DRA polypeptide is an 84,500-Da protein that contains charged clusters of amino acids, primarily at the NH2 and COOH termini [21].

Physical interactions of SLC26A3

  • Activation of CFTR by DRA was facilitated by their PDZ ligands and binding of the SLC26T STAS domain to the CFTR R domain [22].
  • However, DRA differs from other bicarbonate transport proteins because its transport activity is not stimulated by direct interaction with CAII [23].

Regulatory relationships of SLC26A3

  • DRA markedly activates CFTR by increasing its overall open probablity (NP(o)) sixfold [22].
  • To determine whether interaction with CAII affects the downregulated in adenoma (DRA) chloride/bicarbonate exchanger, anion exchange activity of DRA-transfected HEK-293 cells was monitored by following changes in intracellular pH associated with bicarbonate transport [23].
  • Di-/tri- and especially tetrapeptides incorporating the sequence DADD present in the carboxyterminal region of the bicarbonate/chloride anion exchanger AE1 strongly activate human carbonic anhydrase (CA) isozyme II, whereas they act as more inefficient activators of isozymes I and IV [24].
  • In HEK cells, which express little PDZK1, additional transfection of PDZK1 was required for UTP to inhibit DRA [25].

Other interactions of SLC26A3


Analytical, diagnostic and therapeutic context of SLC26A3

  • In this study, in situ hybridization and immunohistochemistry were performed to investigate the expression of CLD in extraintestinal normal epithelia and in intestinal inflammatory and neoplastic epithelia [5].
  • Finally, gel shift analysis showed synergistic complex formation between proteins that bind to the putative X boxes of the DM genes, as is found for the DRA gene [26].
  • The B cell-specific nuclear factor OTF-2 positively regulates transcription of the human class II transplantation gene, DRA [27].
  • Urinary LTE4 levels were significantly elevated in CLD compared with the control group (288 +/- 92 versus 35 +/- 10 pg/mg creatinine, mean +/- SE, p < 0.05) [11].
  • We also identified disease specific antigenic epitopes on CRT molecule, predominantly recognised by IgA Ab of patients suffering from a particular disease: GGYVKLFPNS and YVKLFPNSLD in AIH (83%, 92% of patients), GLQTSQDARF and EQRLKEEEED in CLD (both 75%) and ASKPEDWDER in ALC (67%) [28].


  1. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Liu, X.Z., Ouyang, X.M., Xia, X.J., Zheng, J., Pandya, A., Li, F., Du, L.L., Welch, K.O., Petit, C., Smith, R.J., Webb, B.T., Yan, D., Arnos, K.S., Corey, D., Dallos, P., Nance, W.E., Chen, Z.Y. Hum. Mol. Genet. (2003) [Pubmed]
  2. Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis. Lohi, H., Mäkelä, S., Pulkkinen, K., Höglund, P., Karjalainen-Lindsberg, M.L., Puolakkainen, P., Kere, J. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  3. Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes. Chernova, M.N., Jiang, L., Shmukler, B.E., Schweinfest, C.W., Blanco, P., Freedman, S.D., Stewart, A.K., Alper, S.L. J. Physiol. (Lond.) (2003) [Pubmed]
  4. slc26a3 (dra)-deficient Mice Display Chloride-losing Diarrhea, Enhanced Colonic Proliferation, and Distinct Up-regulation of Ion Transporters in the Colon. Schweinfest, C.W., Spyropoulos, D.D., Henderson, K.W., Kim, J.H., Chapman, J.M., Barone, S., Worrell, R.T., Wang, Z., Soleimani, M. J. Biol. Chem. (2006) [Pubmed]
  5. The congenital chloride diarrhea gene is expressed in seminal vesicle, sweat gland, inflammatory colon epithelium, and in some dysplastic colon cells. Haila, S., Saarialho-Kere, U., Karjalainen-Lindsberg, M.L., Lohi, H., Airola, K., Holmberg, C., Hästbacka, J., Kere, J., Höglund, P. Histochem. Cell Biol. (2000) [Pubmed]
  6. B-cell factor 1 is required for optimal expression of the DRA promoter in B cells. Voliva, C.F., Aronheim, A., Walker, M.D., Peterlin, B.M. Mol. Cell. Biol. (1992) [Pubmed]
  7. Minimum standards for the description of participants in learning disabilities research. CLD Research Committee. Rosenberg, M.S., Bott, D., Majsterek, D., Chiang, B., Gartland, D., Wesson, C., Graham, S., Smith-Myles, B., Miller, M., Swanson, H.L. Journal of learning disabilities. (1993) [Pubmed]
  8. Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Höglund, P., Haila, S., Socha, J., Tomaszewski, L., Saarialho-Kere, U., Karjalainen-Lindsberg, M.L., Airola, K., Holmberg, C., de la Chapelle, A., Kere, J. Nat. Genet. (1996) [Pubmed]
  9. A mutant human histocompatibility leukocyte antigen DR molecule associated with invariant chain peptides. Mellins, E., Cameron, P., Amaya, M., Goodman, S., Pious, D., Smith, L., Arp, B. J. Exp. Med. (1994) [Pubmed]
  10. The down-regulated in adenoma (DRA) gene encodes an intestine-specific membrane glycoprotein. Byeon, M.K., Westerman, M.A., Maroulakou, I.G., Henderson, K.W., Suster, S., Zhang, X.K., Papas, T.S., Vesely, J., Willingham, M.C., Green, J.E., Schweinfest, C.W. Oncogene (1996) [Pubmed]
  11. Elevated urinary leukotriene E4 in chronic lung disease of extreme prematurity. Davidson, D., Drafta, D., Wilkens, B.A. Am. J. Respir. Crit. Care Med. (1995) [Pubmed]
  12. Red blood cell glutathione and plasma sulfhydryls in chronic lung disease of the newborn. Moison, R.M., Haasnoot, A.A., van Zoeren-Grobben, D., Berger, H.M. Acta Paediatr. (1997) [Pubmed]
  13. Hypermanganesemia in long-term intravenous nutrition and chronic liver disease. Wardle, C.A., Forbes, A., Roberts, N.B., Jawhari, A.V., Shenkin, A. JPEN. Journal of parenteral and enteral nutrition. (1999) [Pubmed]
  14. Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea. Höglund, P., Sormaala, M., Haila, S., Socha, J., Rajaram, U., Scheurlen, W., Sinaasappel, M., de Jonge, H., Holmberg, C., Yoshikawa, H., Kere, J. Hum. Mutat. (2001) [Pubmed]
  15. Identification of an apical Cl(-)/HCO3(-) exchanger in the small intestine. Wang, Z., Petrovic, S., Mann, E., Soleimani, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  16. Human DRA functions as a sulfate transporter in Sf9 insect cells. Byeon, M.K., Frankel, A., Papas, T.S., Henderson, K.W., Schweinfest, C.W. Protein Expr. Purif. (1998) [Pubmed]
  17. Chloride and bicarbonate have similar affinities to the intestinal anion exchanger DRA (down regulated in adenoma). Lamprecht, G., Schaefer, J., Dietz, K., Gregor, M. Pflugers Arch. (2006) [Pubmed]
  18. The CFTR associated protein CAP70 interacts with the apical Cl-/HCO3- exchanger DRA in rabbit small intestinal mucosa. Rossmann, H., Jacob, P., Baisch, S., Hassoun, R., Meier, J., Natour, D., Yahya, K., Yun, C., Biber, J., Lackner, K.J., Fiehn, W., Gregor, M., Seidler, U., Lamprecht, G. Biochemistry (2005) [Pubmed]
  19. The SLC26 gene family of multifunctional anion exchangers. Mount, D.B., Romero, M.F. Pflugers Arch. (2004) [Pubmed]
  20. SLC26 transporters and the inhibitory control of pancreatic ductal bicarbonate secretion. Hegyi, P., Rakonczay, Z., Tiszlavicz, L., Varr??, A., T??th, A., R??cz, G., Varga, G., Gray, M.A., Argent, B.E. Novartis Found. Symp. (2006) [Pubmed]
  21. Identification of a colon mucosa gene that is down-regulated in colon adenomas and adenocarcinomas. Schweinfest, C.W., Henderson, K.W., Suster, S., Kondoh, N., Papas, T.S. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  22. Gating of CFTR by the STAS domain of SLC26 transporters. Ko, S.B., Zeng, W., Dorwart, M.R., Luo, X., Kim, K.H., Millen, L., Goto, H., Naruse, S., Soyombo, A., Thomas, P.J., Muallem, S. Nat. Cell Biol. (2004) [Pubmed]
  23. The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II. Sterling, D., Brown, N.J., Supuran, C.T., Casey, J.R. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  24. Carbonic anhydrase activators: human isozyme II is strongly activated by oligopeptides incorporating the carboxyterminal sequence of the bicarbonate anion exchanger AE1. Scozzafava, A., Supuran, C.T. Bioorg. Med. Chem. Lett. (2002) [Pubmed]
  25. Intestinal anion exchanger down-regulated in adenoma (DRA) is inhibited by intracellular calcium. Lamprecht, G., Hsieh, C.J., Lissner, S., Nold, L., Heil, A., Gaco, V., Schäfer, J., Turner, J.R., Gregor, M. J. Biol. Chem. (2009) [Pubmed]
  26. HLA-DMA and HLA-DMB gene expression functions through the conserved S-X-Y region. Westerheide, S.D., Louis-Plence, P., Ping, D., He, X.F., Boss, J.M. J. Immunol. (1997) [Pubmed]
  27. The B cell-specific nuclear factor OTF-2 positively regulates transcription of the human class II transplantation gene, DRA. Zeleznik-Le, N.J., Itoh-Lindstrom, Y., Clarke, J.B., Moore, T.L., Ting, J.P. J. Biol. Chem. (1992) [Pubmed]
  28. Epitopes of calreticulin recognised by IgA autoantibodies from patients with hepatic and coeliac disease. Sánchez, D., Tucková, L., Mothes, T., Kreisel, W., Benes, Z., Tlaskalová-Hogenová, H. J. Autoimmun. (2003) [Pubmed]
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