Sulfate transporter

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.

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]

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.