Article: article from journal or magazin.
Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
American Journal of Human Genetics
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. Publication Status: ppublish
Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD). The similarity suggests a shared pathogenesis involving lesions in the same biochemical pathway and perhaps the same gene. DTD is caused by mutations in the recently identified diastrophic dysplasia sulfate-transporter gene (DTDST). Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate 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 appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein.
Anion Transport Proteins, Base Sequence, Biological Transport, Bone and Bones/ultrastructure, Carrier Proteins/genetics, Cloning, Molecular, Fibroblasts, Gene Expression/genetics, Heterozygote, Humans, Infant, Newborn, Membrane Transport Proteins, Molecular Sequence Data, Osteochondrodysplasias/genetics, Osteochondrodysplasias/metabolism, Osteogenesis, Point Mutation/genetics, Proteoglycans/biosynthesis, Proteoglycans/genetics, Sequence Analysis, Sequence Deletion/genetics, Sulfates/metabolism
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