The sulfate transporter is a solute carrier familyprotein that in humans is encoded by the SLC26A2gene.[5] SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994.[5] A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B[6] was subsequently also found to be caused by genetic variants in the sulfate transporter gene.[7] This sulfate (SO42−) transporter also accepts chloride, hydroxyl ions (OH−), and oxalate as substrates.[8][9] SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.[10][11]
Function
The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. In chondrocytes, SLC26A2 functions to transport most of the cellular sulfate, which is critical for the sulfation of proteoglycans and normal cartilage formation.[12] In addition, studies have demonstrated that SLC26A2 influences chondrocyte proliferation, differentiation, and growth, suggesting that in the chondrocyte, SLC26A2 provides sulfate for both structural and regulatory proteins.[13]
Since its first description, over 30 mutations in the SLC26A2 gene have been described in the four recessively inherited chondrodysplasias listed above. Achondrogenesis 1B (ACG-1B) is the most severe form of these chondrodysplasias, resulting in skeletal underdevelopment and death preceding or shortly after birth.[15] Atelosteogenesis type II (AO-II) can be lethal in the neonatal period,[16] whereas diastrophic dysplasia (DTD) and autosomal recessive multiple epiphyseal dysplasia (EDM4/rMED) are considered to be the least severe forms.
When ten previously described SLC26A2 mutation were expressed in mammalian cells, a strong correlation was found between the amount of sulfate transport activity of the mutated protein and the severity of the phenotype in patients where these mutations have been identified.[17] For example, a mutation that results in a non-functional protein on both alleles was always found with the severe ACG-IB phenotype, but non-functional mutations on both alleles were never found with the less severe phenotypes, DTD and rMED. Mutations found in the moderately severe AO-II phenotype were always the result of a non-functioning mutation on one allele and a partial-functioning mutation on the opposite allele. In contrast, mutations described in the mildest form of the chondrodysplasia, rMED, result in proteins that retain at least some partial sulfate transport function on both alleles. This suggests that even a small amount of SLC26A2-mediated sulfate transport in chondrocytes can mitigate the clinical severity of the chondrodysplasia. However, a less predictable genotype/phenotype correlation has been found with a mutation described predominately in the Finnish population. This Finnish mutation is located in the splice site of the gene and results in low SLC26A2 mRNA levels.[18] Different levels of expression of the SLC26A2 protein is probably the cause of the variable phenotypes described with this mutation.
Functional significance of SLC26A2 in the colon and the kidney
Immunohistochemical analysis has localized SLC26A2 to the apical membrane of colon epithelial cells and kidney proximal tubule cells.[8][19]
Colon
Abundant SLC26A2 mRNA levels have been identified in the small and large intestine of mice, rats and humans. In the human colon, SLC26A2 is present in the upper third of the crypts, where it is directed toward the apical membrane.[20] The physiological role of SLC26A2 in the human colon remains to be determined, but it likely represent the sulfate/oxalate exchanger that has been characterized in colonic apical membrane vesicle preparations and possibly plays an important role in sulfate transport in this tissue.[21] In fact, impaired sulfation has been suggested to occur during the course of malignant transformation of colonic epithelial cells, and studies have shown that the growth rate of cancer cells was markedly enhanced when the transcription of SLC26A2 was suppressed.[22]
Kidney
The SLC26A2 protein has been localized to the brush border membrane of the rat kidney proximal tubule.[19] In that location, oxalate/SO42− exchange, or chloride/SO42− exchange by SLC26A2 might contribute to the critical process of sodium chloride reabsorption across the proximal tubular epithelium. Under one proposed model, an anion transporter exchanges intracellular oxalate for luminal chloride in parallel with the Na–SO4 cotransporter, resulting in net sodium chloride readsorption.[23] Under this model, a third transport process is required that functions as a method of recycling oxalate back into the cell, and recycling sulfate from the cell to the lumen. Previously, SLC26A6, another member of the same family of anion transporters as DTDST, was thought to provide the mechanism of oxalate- or formate-mediated chloride transport in this nephron segment; however, recent studies in Slc26a6-knockout mice have raised questions regarding its role in this transport process.[24] In contrast, the apical membrane location, and electrochemical properties of SLC26A2 would fit the requirement of an anion exchanger located on the apical membrane of the proximal tubule that would serve as a mechanism of transporting chloride in exchange for oxalate, and/or recycling oxalate in exchange for sulfate.
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ abHästbacka J, de la Chapelle A, Mahtani MM, Clines G, Reeve-Daly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A (September 1994). "The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping". Cell. 78 (6): 1073–87. doi:10.1016/0092-8674(94)90281-X. PMID7923357. S2CID36181375.
^Superti-Furga A, Hästbacka J, Wilcox WR, Cohn DH, van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R (January 1996). "Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene". Nature Genetics. 12 (1): 100–2. doi:10.1038/ng0196-100. PMID8528239. S2CID31143438.
^Superti-Furga A, Hästbacka J, Rossi A, van der Harten JJ, Wilcox WR, Cohn DH, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R. A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. Ann N Y Acad Sci. 1996 Jun 8;785:195-201. doi: 10.1111/j.1749-6632.1996.tb56259.x. PMID: 8702127.
^Superti-Furga A, Hästbacka J, Wilcox WR, Cohn DH, van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R (January 1996). "Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene". Nature Genetics. 12 (1): 100–2. doi:10.1038/ng0196-100. PMID8528239. S2CID31143438.
^Haila S, Saarialho-Kere U, Karjalainen-Lindsberg ML, Lohi H, Airola K, Holmberg C, Hästbacka J, Kere J, Höglund P (April 2000). "The congenital chloride diarrhea gene is expressed in seminal vesicle, sweat gland, inflammatory colon epithelium, and in some dysplastic colon cells". Histochemistry and Cell Biology. 113 (4): 279–86. doi:10.1007/s004180000131. PMID10857479. S2CID10999468.
^Tyagi S, Kavilaveettil RJ, Alrefai WA, Alsafwah S, Ramaswamy K, Dudeja PK (November 2001). "Evidence for the existence of a distinct SO(4)(--)-OH(-) exchange mechanism in the human proximal colonic apical membrane vesicles and its possible role in chloride transport". Experimental Biology and Medicine. 226 (10): 912–8. doi:10.1177/153537020122601006. PMID11682697. S2CID24469074.
Rossi A, Kaitila I, Wilcox WR, Rimoin DL, Steinmann B, Cetta G, Superti-Furga A (October 1998). "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". Matrix Biology. 17 (5): 361–9. doi:10.1016/S0945-053X(98)90088-9. PMID9822202.
Mégarbané A, Haddad FA, Haddad-Zebouni S, Achram M, Eich G, Le Merrer M, Superti-Furga A (July 1999). "Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia". Clinical Genetics. 56 (1): 71–6. doi:10.1034/j.1399-0004.1999.560110.x. PMID10466420. S2CID19411099.
Mäkitie O, Savarirayan R, Bonafé L, Robertson S, Susic M, Superti-Furga A, Cole WG (October 2003). "Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign". American Journal of Medical Genetics. Part A. 122A (3): 187–92. doi:10.1002/ajmg.a.20282. PMID12966518. S2CID1814933.
Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M, Kere J (November 2000). "Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger". Genomics. 70 (1): 102–12. doi:10.1006/geno.2000.6355. PMID11087667.
Huang QY, Li GH, Kung AW (August 2009). "The -9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPalpha and FOXA1 binding is associated with osteoporosis". Bone. 45 (2): 289–94. doi:10.1016/j.bone.2009.03.676. PMID19371798.
Bonafé L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A (2014-01-23). "SLC26A2-Related Multiple Epiphyseal Dysplasia". Multiple Epiphyseal Dysplasia, Recessive. University of Washington, Seattle. PMID20301483. NBK1306. In Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (2002). Pagon RA, Bird TD, Dolan CR, et al. (eds.). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle. PMID20301295.
Luisa B, Mittaz-Crettol L, Ballhausen D, Superti-Furga A (2014-01-23). "SLC26A2-Related Atelosteogenesis". Atelosteogenesis Type 2. University of Washington, Seattle. PMID20301493. NBK1317. In GeneReviews
