The
diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane
protein that transports
sulfate into chondrocytes to maintain adequate sulfation of
proteoglycans. Mutations in this gene are responsible for four recessively inherited chondrodysplasias that include
diastrophic dysplasia,
multiple epiphyseal dysplasia,
atelosteogenesis type 2 and
achondrogenesis 1B (ACG-1B). To determine whether the DTDST mutations found in individuals with these chondrodysplasias differ functionally from each other, we compared the
sulfate transport activity of 11 reported DTDST mutations. Five mutations, G255E, Delta a1751, L483P, R178X and N425D, had minimal
sulfate transport function following expression in Xenopus laevis oocytes. Two mutations, Delta V340 and R279W, transported
sulfate at rates of 17 and 32%, respectively, of wild-type DTDST. Four mutations, A715V, C653S, Q454P and G678V, had rates of
sulfate transport nearly equal to that of wild-type DTDST. Transport kinetics were not different among the four mutations with near-normal
sulfate transport function and wild-type DTDST. When the
sulfate transport function of the different DTDST mutations are grouped according to the general phenotypes, individuals with the most severe form, ACG-1B, tend to be homozygous for null mutations, individuals with the moderately severe
atelosteogenesis type 2 have at least one allele with a loss-of-function mutation, and individuals with the mildest forms are typically homozygous for mutations with residual
sulfate transport function. However, in the X.laevis oocyte expression system, the correlation between residual transport function and the severity of phenotype was not absolute, suggesting that factors in addition to the intrinsic
sulfate transport properties of the DTDST
protein may influence the phenotype in individuals with DTDST mutations.