Sulfate transporter explained

The sulfate transporter is a solute carrier family protein that in humans is encoded by the SLC26A2 gene.^[1] SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B^[2] was subsequently also found to be caused by genetic variants in the sulfate transporter gene.^[3] This sulfate (SO₄²⁻) transporter also accepts chloride, hydroxyl ions (OH⁻), and oxalate as substrates.^{[4] [5]} SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.^[6]

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.^[7] 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.^[8]

Clinical significance

Deficiencies are associated with many forms of osteochondrodysplasia.^{[9] [10]} These include:

• achondrogenesis type 1B
• diastrophic dysplasia
• atelosteogenesis, type II
• recessive multiple epiphyseal dysplasia

Correlation between genotype and phenotype

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.^[11] Atelosteogenesis type II (AO-II) can be lethal in the neonatal period,^[12] 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.^[13] 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.^[14] 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.^[15]

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.^[16] 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.^[17] 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.^[18]

Kidney

The SLC26A2 protein has been localized to the brush border membrane of the rat kidney proximal tubule. 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.^[19] 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.^[20] 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.

Further reading

• Rossi A, Kaitila I, Wilcox WR, Rimoin DL, Steinmann B, Cetta G, Superti-Furga A . 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 . October 1998 . 9822202 . 10.1016/S0945-053X(98)90088-9 .
• Jakkula E, Mäkitie O, Czarny-Ratajczak M, Czarny-Ratacjzak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L . Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations . European Journal of Human Genetics . 13 . 3 . 292–301 . March 2005 . 15523498 . 10.1038/sj.ejhg.5201314 . free .
• Bonafé L, Hästbacka J, de la Chapelle A, Campos-Xavier AB, Chiesa C, Forlino A, Superti-Furga A, Rossi A . A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia . Journal of Medical Genetics . 45 . 12 . 827–31 . December 2008 . 18708426 . 4361899 . 10.1136/jmg.2007.057158 .
• Lohi H, Kujala M, Makela S, Lehtonen E, Kestila M, Saarialho-Kere U, Markovich D, Kere J . Functional characterization of three novel tissue-specific anion exchangers SLC26A7, -A8, and -A9 . The Journal of Biological Chemistry . 277 . 16 . 14246–54 . April 2002 . 11834742 . 10.1074/jbc.M111802200 . free .
• Lamb R, Thomson W, Ogilvie EM, Donn R . Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic-onset juvenile idiopathic arthritis . Arthritis and Rheumatism . 56 . 4 . 1286–91 . April 2007 . 17393463 . 10.1002/art.22444 .
• Ikeda T, Mabuchi A, Fukuda A, Hiraoka H, Kawakami A, Yamamoto S, Machida H, Takatori Y, Kawaguchi H, Nakamura K, Ikegawa S . Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis . Journal of Human Genetics . 46 . 9 . 538–43 . 2001 . 11558903 . 10.1007/s100380170036 . free .
• Mégarbané A, Haddad FA, Haddad-Zebouni S, Achram M, Eich G, Le Merrer M, Superti-Furga A . Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia . Clinical Genetics . 56 . 1 . 71–6 . July 1999 . 10466420 . 10.1034/j.1399-0004.1999.560110.x . 19411099 .
• Markovich D . Physiological roles and regulation of mammalian sulfate transporters . Physiological Reviews . 81 . 4 . 1499–533 . October 2001 . 11581495 . 10.1152/physrev.2001.81.4.1499 . 30942862 .
• Pecora F, Gualeni B, Forlino A, Superti-Furga A, Tenni R, Cetta G, Rossi A . In vivo contribution of amino acid sulfur to cartilage proteoglycan sulfation . The Biochemical Journal . 398 . 3 . 509–14 . September 2006 . 16719839 . 1559448 . 10.1042/BJ20060566 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .
• Satoh H, Susaki M, Shukunami C, Iyama K, Negoro T, Hiraki Y . Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfated proteoglycans . The Journal of Biological Chemistry . 273 . 20 . 12307–15 . May 1998 . 9575183 . 10.1074/jbc.273.20.12307 . free .
• Mäkitie O, Savarirayan R, Bonafé L, Robertson S, Susic M, Superti-Furga A, Cole WG . 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 . October 2003 . 12966518 . 10.1002/ajmg.a.20282 . 1814933 .
• Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M, Kere J . 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 . November 2000 . 11087667 . 10.1006/geno.2000.6355 .
• Galante LL, Schwarzbauer JE . Requirements for sulfate transport and the diastrophic dysplasia sulfate transporter in fibronectin matrix assembly . The Journal of Cell Biology . 179 . 5 . 999–1009 . December 2007 . 18056413 . 2099202 . 10.1083/jcb.200707150 .
• Rossi A, Cetta G, Piazza R, Bonaventure J, Steinmann B, Supereti-Furga A . In vitro proteoglycan sulfation derived from sulfhydryl compounds in sulfate transporter chondrodysplasias . Pediatric Pathology & Molecular Medicine . 22 . 4 . 311–21 . 2003 . 14692227 . 10.1080/15227950307720 .
• Remes VM, Hästbacka JR, Poussa MS, Peltonen JI . Does genotype predict development of the spinal deformity in patients with diastrophic dysplasia? . European Spine Journal . 11 . 4 . 327–31 . August 2002 . 12193993 . 3610472 . 10.1007/s00586-002-0413-y .
• Haila S, Hästbacka J, Böhling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U . SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types . The Journal of Histochemistry and Cytochemistry . 49 . 8 . 973–82 . August 2001 . 11457925 . 10.1177/002215540104900805 . free .
• Huang QY, Li GH, Kung AW . 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 . August 2009 . 19371798 . 10.1016/j.bone.2009.03.676 .
• Book: Bonafé L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A . 2014-01-23 . Multiple Epiphyseal Dysplasia, Recessive . SLC26A2-Related Multiple Epiphyseal Dysplasia . University of Washington, Seattle . 20301483 . NBK1306 . In Book: Pagon RA, Bird TD, Dolan CR . GeneReviews [Internet] ]. 2002 . University of Washington, Seattle . Seattle WA . 20301295 . . etal . Adam . M. P. . Feldman . J. . Mirzaa . G. M. . Pagon . R. A. . Wallace . S. E. . Bean LJH . Gripp . K. W. . Amemiya . A. .
• Book: Luisa B, Mittaz-Crettol L, Ballhausen D, Superti-Furga A . 2014-01-23 . Atelosteogenesis Type 2 . SLC26A2-Related Atelosteogenesis . University of Washington, Seattle . 20301493 . NBK1317 . In
• Book: Luisa B, Mittaz-Crettol L, Ballhausen D, Superti-Furga A . 2013-07-18 . Diastrophic Dysplasia . University of Washington, Seattle . 20301524 . NBK1350 . In

Notes and References

1. Hästbacka J, de la Chapelle A, Mahtani MM, Clines G, Reeve-Daly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A . The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping . Cell . 78 . 6 . 1073–87 . September 1994 . 7923357 . 10.1016/0092-8674(94)90281-X . 36181375 .
2. Superti-Furga A . A defect in the metabolic activation of sulfate in a patient with achondrogenesis type IB . American Journal of Human Genetics . 55 . 6 . 1137–45 . December 1994 . 7977372 . 1918434 .
3. 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 . Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene . Nature Genetics . 12 . 1 . 100–2 . January 1996 . 8528239 . 10.1038/ng0196-100 . 31143438 .
4. Heneghan JF, Akhavein A, Salas MJ, Shmukler BE, Karniski LP, Vandorpe DH, Alper SL . Regulated transport of sulfate and oxalate by SLC26A2/DTDST . American Journal of Physiology. Cell Physiology . 298 . 6 . C1363-75 . June 2010 . 20219950 . 10.1152/ajpcell.00004.2010 . 2889644 .
5. Ohana E, Shcheynikov N, Park M, Muallem S . Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SOFormula/OH-/Cl- exchanger regulated by extracellular Cl- . The Journal of Biological Chemistry . 287 . 7 . 5122–32 . February 2012 . 22190686 . 10.1074/jbc.M111.297192 . 3281620 . free .
6. Haila S, Hästbacka J, Böhling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U . SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types . The Journal of Histochemistry and Cytochemistry . 49 . 8 . 973–82 . August 2001 . 11457925 . 10.1177/002215540104900805 . free .
7. Web site: Entrez Gene: SLC26A2.
8. Park M, Ohana E, Choi SY, Lee MS, Park JH, Muallem S . Multiple roles of the SO4(2-)/Cl-/OH- exchanger protein Slc26a2 in chondrocyte functions . The Journal of Biological Chemistry . 289 . 4 . 1993–2001 . January 2014 . 24302720 . 10.1074/jbc.M113.503466 . 3900949 . free .
9. 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.
10. Forlino A, Piazza R, Tiveron C, Della Torre S, Tatangelo L, Bonafè L, Gualeni B, Romano A, Pecora F, Superti-Furga A, Cetta G, Rossi A . A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype . Human Molecular Genetics . 14 . 6 . 859–71 . March 2005 . 15703192 . 10.1093/hmg/ddi079 . free .
11. 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 . Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene . Nature Genetics . 12 . 1 . 100–2 . January 1996 . 8528239 . 10.1038/ng0196-100 . 31143438 .
12. Hästbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES . Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias . American Journal of Human Genetics . 58 . 2 . 255–62 . February 1996 . 8571951 . 1914552 .
13. Karniski LP . Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells . Human Molecular Genetics . 13 . 19 . 2165–71 . October 2004 . 15294877 . 10.1093/hmg/ddh242 . free .
14. Hästbacka J, Kerrebrock A, Mokkala K, Clines G, Lovett M, Kaitila I, de la Chapelle A, Lander ES . Identification of the Finnish founder mutation for diastrophic dysplasia (DTD) . European Journal of Human Genetics . 7 . 6 . 664–70 . September 1999 . 10482955 . 10.1038/sj.ejhg.5200361 . free .
15. Chapman JM, Karniski LP . Protein localization of SLC26A2 (DTDST) in rat kidney . Histochemistry and Cell Biology . 133 . 5 . 541–7 . May 2010 . 20369363 . 10.1007/s00418-010-0694-x . 13591652 .
16. Haila S, Saarialho-Kere U, Karjalainen-Lindsberg ML, Lohi H, Airola K, Holmberg C, Hästbacka J, Kere J, Höglund P . 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 . April 2000 . 10857479 . 10.1007/s004180000131. 10999468 .
17. Tyagi S, Kavilaveettil RJ, Alrefai WA, Alsafwah S, Ramaswamy K, Dudeja PK . 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 . November 2001 . 11682697 . 10.1177/153537020122601006. 24469074 .
18. Yusa A, Miyazaki K, Kimura N, Izawa M, Kannagi R . Epigenetic silencing of the sulfate transporter gene DTDST induces sialyl Lewisx expression and accelerates proliferation of colon cancer cells . Cancer Research . 70 . 10 . 4064–73 . May 2010 . 20460514 . 10.1158/0008-5472.CAN-09-2383 . free .
19. Kuo SM, Aronson PS . Pathways for oxalate transport in rabbit renal microvillus membrane vesicles . The Journal of Biological Chemistry . 271 . 26 . 15491–7 . June 1996 . 8663096 . 10.1074/jbc.271.26.15491. free .
20. Knauf F, Velazquez H, Pfann V, Jiang Z, Aronson PS. January 2019. Characterization of renal NaCl and oxalate transport in Slc26a6 -/- mice. American Journal of Physiology. Renal Physiology. 316. 1. F128–F133. 10.1152/ajprenal.00309.2018. 6383200. 30427220.