Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype.
Two sulfation-related genes have been reported as the causal genes of severe chondrodysplasias: mutations in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2) cause spondylo-epimetaphyseal dysplasia (SEMD), and mutations in SLC26A2 (solute carrier family 26, member 2) cause diastrophic dysplasia.
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.
The expression of the closely related anion transporter diastrophic dysplasiasulfate transporter, DTDST, was also examined and compared with that of CLD in colon.
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%).
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.
Undersulfation of cartilage proteoglycans ex vivo and increased contribution of amino acid sulfur to sulfation in vitro in McAlister dysplasia/atelosteogenesis type 2.
Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
A substantial portion of remaining patients have mutations of the genes encoding cartilage oligomeric matrix protein or diastrophic dysplasiasulfate transporter.
Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution 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.
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.