title: Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
abstract: 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, USA. johanna.hastbacka@helsinki.fi
authors.forename: J
authors.initials: J
authors.lastname: Hästbacka
authors.forename: A
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: W R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: D L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: D H
authors.initials: DH
authors.lastname: Cohn
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D027321:Anion Transport Proteins; D001483:Base Sequence; D001692:Biological Transport; D001842:Bone and Bones / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics*; D003001:Cloning, Molecular; D005347:Fibroblasts; D015870:Gene Expression / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism; D010012:Osteogenesis; D017354:Point Mutation / Q000235:genetics; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017421:Sequence Analysis; D017384:Sequence Deletion / Q000235:genetics; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism*
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D011509:Proteoglycans; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters; D013431:Sulfates