Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype

The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transm embrane protein that transports sulfate into chondrocytes to maintain adequ ate sulfation of proteoglycans. Mutations in this gene are responsible for four recessively inherited chondrodysplasias that include diastrophic dyspl asia, multiple epiphyseal dysplasia, atelosteogenesis type 2 and achondroge nesis 1B (ACG-1B). To determine whether the DTDST mutations found in indivi duals with these chondrodysplasias differ functionally from each other, we compared the sulfate transport activity of 11 reported DTDST mutations. Fiv e mutations, G255E, Delta a1751, L483P, R178X and N425D, had minimal sulfat e transport function following expression in Xenopus laevis oocytes. Two mu tations, Delta V340 and R279W, transported sulfate at rates of 17 and 32%, respectively, of wild-type DTDST. Four mutations, A715V, C653S, Q454P and G 678V, had rates of sulfate transport nearly equal to that of wild-type DTDS T. Transport kinetics were not different among the four mutations with near -normal sulfate transport function and wild-type DTDST. When the sulfate tr ansport 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 sever e atelosteogenesis type 2 have at least one allele with a loss-of-function mutation, and individuals with the mildest forms are typically homozygous f or mutations with residual sulfate transport function. However, in the X.la evis oocyte expression system, the correlation between residual transport f unction and the severity of phenotype was not absolute, suggesting that fac tors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations.