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

• Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis [2].
• The combined PCR-SSCP and sequencing analyses revealed altogether seven novel mutations including two missense mutations (S206P, D468V), two splicing defects (IVS12-1G>C, IVS13-2delA), one nonsense mutation (Q436X), one insertion/deletion mutation (2104-2105delGGins29-bp), and an intragenic deletion of SLC26A3 exons 7 and 8 [14].
• Tissue distribution studies indicated that the expression of PAT1 is highly abundant in the small intestine but is low in the colon, a pattern opposite that of DRA [15].
• We have previously shown that DRA proteins are found as various forms in tissue due to differential glycosylation [16].
• An ion transport assay demonstrated that DRA functions as a sulfate transporter [16].

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

• Expression of CFTR and SLC26A3 proteins were determined by immunohistochemistry and Western blotting from the same samples, respectively [2].
• Expression levels of the cystic fibrosis transmembrane regulator (CFTR) (Cl- channel), SLC26A3 (Cl-/HCO exchanger) and SLC9A3 (Na+/H+ exchanger) mRNAs were measured by real-time quantitative RT-PCR in peroperative colonic samples from controls (n = 4) and patients with ulcerative colitis (n = 10) [2].
• The interaction was recapitulated in HEK cells transfected with DRA and PDZK1, the human orthologue of CAP70 [18].
• The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II [23].
• Compared with AE1, the COOH-terminal tail of DRA interacted weakly with CAII [23].

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].

References