Disease relevance of SLC26A2

• Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis [1].
• Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation [2].
• Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man [3].
• Metabolism of MC by rat and human E. coli DTD was also compared under aerobic and hypoxic conditions [4].
• In contrast, the toxicity of MC to DTD-deficient BE cells was potentiated markedly under hypoxia [4].

High impact information on SLC26A2

• A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene (SLC26A) [5].
• On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter [6].
• DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus [7].
• Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities [7].
• Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping [7].

Chemical compound and disease context of SLC26A2

• The antitumor compounds were reduced in the following order by rat E. coli DTD: 2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone > streptonigrin > mitomycin A > diaziquone > mitomycin C (MC) > 5-(aziridin-1-yl)-2,4-dinitrobenzamide [4].
• Km and kcat values for menadione and 2,6-dichlorophenolindophenol reduction were similar for the three enzyme preparations except that rat E. coli DTD had 2-3-fold higher kcat values for both menadione and 2,6-dichlorophenolindophenol and a 2-3-fold higher Km for menadione than either rat liver or human E. coli DTD [4].
• The order was the same for human E. coli DTD with one exception; diaziquone was reduced slightly faster than mitomycin A [4].
• Metabolism of doxorubicin could not be detected using rat or human E. coli DTD [4].
• The HT-29 cell line was only vulnerable to NQ and MEN after inhibition of DT-diaphorase (DTD) with dicoumarol, whereas dicoumarol did not affect the toxicity of quinones to Caco-2 cells [8].

Biological context of SLC26A2

• Given their critical roles in cartilage metabolism and the severe phenotypes that result from mutations in these genes, we examined PAPSS2 and SLC26A2 as candidate susceptibility loci for OA [1].
• An association analysis showed suggestive association of one minor polymorphism in the promoter region of SLC26A2 [1].
• An ion transport assay demonstrated that DRA functions as a sulfate transporter [9].
• FISH-mapping of LEP and SLC26A2 genes in sheep, goat and cattle R-banded chromosomes: comparison between bovine, ovine and caprine chromosome 4 (BTA4/OAR4/CHI4) and human chromosome 7 (HSA7) [10].
• Analysis of the genomic sequence revealed that the rat DTDST gene was composed of at least five exons [11].

Anatomical context of SLC26A2

• Tat1, a novel sulfate transporter specifically expressed in human male germ cells and potentially linked to rhogtpase signaling [12].
• Therefore we conclude that Tat1 is a novel sulfate transporter specifically expressed in spermatocytes and spermatids and interacts with MgcRacGAP in these cells [12].
• He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders [2].
• Molecular and functional characterization of SLC26A11, a sodium-independent sulfate transporter from high endothelial venules [13].
• In addition, immunoreactivity for the SLC26A2 protein was observed in exocrine pancreas [14].

Associations of SLC26A2 with chemical compounds

• Together, our results indicate that SLC26A11 is a novel Na+-independent sulfate transporter that may cooperate with SLC26A2 to mediate DIDS-sensitive sulfate uptake into HEVEC [13].
• SLC26A2 acts as an Na(+)-independent sulfate/chloride antiporter and belongs to the SLC26 anion transporter gene family, currently consisting of six homologous human members [14].
• To evaluate the degree of proteoglycan undersulfation in vivo, we have extracted chondroitin sulfate proteoglycans from cartilage of twelve patients with sulfate transporter chondrodysplasias and analyzed their disaccharide composition by HPLC after digestion with chondroitinase ABC [15].
• When both compounds were tested in primary chondrocytes from a DTD patient, partial rescue of PG sulfation was observed, suggesting that the metabolic pathways producing cytoplasmic sulfate from thiols are also active in this cell type [16].
• We have studied the contribution of cysteine and its derivatives to PG sulfation in fibroblast and chondrocyte cultures from sulfate transporter dysplasia patients [16].

Physical interactions of SLC26A2

• Together, these results demonstrate that SUT-1 is a distinct human Na(+)-coupled sulfate transporter, likely to play a major role in sulfate incorporation in HEV [17].

Other interactions of SLC26A2

• Ten sequence polymorphisms were detected in PAPSS2 and five in SLC26A2 [1].
• The expression of the closely related anion transporter diastrophic dysplasia sulfate transporter, DTDST, was also examined and compared with that of CLD in colon [18].
• One presumptive candidate gene, osteonectin (SPARC), could be excluded on the basis of three recombinations with the DTD locus [19].
• Molecular cloning and functional analysis of SUT-1, a sulfate transporter from human high endothelial venules [17].
• Exclusion of the COL2A1 gene as the mutation site in diastrophic dysplasia [20].

Analytical, diagnostic and therapeutic context of SLC26A2

• Abundant SLC26A2 expression has previously been detected in normal human colon by in situ hybridization [14].
• Direct sequence analysis of genomic DNA demonstrated a homozygous 1984T > A (C653S) change in the DTDST gene in all patients [21].
• Northern blot analysis suggested that cartilage and intestine were the major expression sites for DTDST mRNA [11].
• Proteoglycan sulfation in cartilage and cell cultures from patients with sulfate transporter chondrodysplasias: relationship to clinical severity and indications on the role of intracellular sulfate production [15].
• The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts [22].

References