ATELOSTEOGENESIS TYPE-II IS CAUSED BY MUTATIONS IN THE DIASTROPHIC DYSPLASIA SULFATE-TRANSPORTER GENE (DTDST) - EVIDENCE FOR A PHENOTYPIC SERIES INVOLVING 3 CHONDRODYSPLASIAS

Atelosteogenesis type II (AO II) is a neonatally Lethal chondrodysplas ia whose clinical and histological characteristics resemble those of a nother chondrodysplasia, the much less severe diastrophic dysplasia (D TD). The similarity suggests a shared pathogenesis involving lesions i n the same biochemical pathway and perhaps the same gene. DTD is cause d by mutations in the recently identified diastrophic dysplasia sulfat e-transporter gene (DTDST). Here, we report that AOII patients also ha ve DTDST mutations, which lead to defective uptake of inorganic sulfat e and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene. The severity of the phenotype appe ars to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein.