Using mesenchymal stem cells (MSCs) in an in vitro chondrogenesis assay, we found that knockdown of the diastrophic dysplasia (DTD) sulfate transporter (DTDST, also known as SLC26A2), which is required for normal cartilage development, blocked cell condensation and caused a significant reduction in fibronectin matrix.
Importantly, mutations in SLC26A2, A3, A4, and A5 have been associated with distinct human genetic recessive disorders (i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues.
Mutations in the sulfate transporter gene, SCL26A2, lead to cartilage proteoglycan undersulfation resulting in chondrodysplasia in humans; the phenotype is mirrored in the diastrophic dysplasia (dtd) mouse.
The fetus affected by McAlister dysplasia we have studied is a compound heterozygote for mutations leading to R279W and N425D substitutions in the diastrophic dysplasiasulfate transporter.
Five fetuses in families with a previous history of DTD were studied by typing them and their relevant family members for DNA markers closely linked to the DTD gene.
A homozygous R279W mutation was recently found in the diastrophic dysplasiasulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella.
Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0.06 centimorgans (or about 60 kilobases) of the CSF1R gene.
The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasiasulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates.
A substantial portion of remaining patients have mutations of the genes encoding cartilage oligomeric matrix protein or diastrophic dysplasiasulfate transporter.
Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasiasulfate transporter (encoded by DTD; 32%) and the human sulfate transporter 'downregulated in adenoma' (encoded by DRA; 45%).
Due to similarities in the clinical phenotype between diastrophic dysplasia and this condition, testing for DTDST mutation was performed with no mutation detected.
These findings reveal multiple roles for Slc26a2 in chondrocyte biology and emphasize the importance of Slc26a2-mediated protein sulfation in cell signaling, which may account for the complex phenotype of DTD.
Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene result in a family of skeletal dysplasias, which comprise lethal (achondrogenesis type 1B and atelosteogenesis type 2) and non-lethal conditions (diastrophic dysplasia and recessive multiple epiphyseal dysplasia (rMED)).
Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype.
Mutations in the sulfate transporter gene SLC26A2 (DTDST) cause a continuum of skeletal dysplasia phenotypes that includes achondrogenesis type 1B (ACG1B), atelosteogenesis type 2 (AO2), diastrophic dysplasia (DTD), and recessive multiple epiphyseal dysplasia (rMED).
The expression of the closely related anion transporter diastrophic dysplasiasulfate transporter, DTDST, was also examined and compared with that of CLD in colon.
Pathogenic sequence variants in the solute carrier family 26 member 2 (SLC26A2) gene result in lethal (achondrogenesis Ib and atelosteogenesis II) and non-lethal (diastrophic dysplasia and recessive multiple epiphyseal dysplasia, rMED) chondrodysplasias.