A Defect intheMetabolic Activation ofSulfate inaPatient with Achondrogenesis TypeIB

Summary Achondrogenesis type Iisaperinatally lethal, short-limb chondrodysplasia. Twotypes, IAandIB,have been distinguished byradiographic andhistological criteria; both types appear tobeinherited asautosomal recessive traits. Theunderlying molecular defects arenotknown, buthistochemical studies have suggested that inachondrogenesis type IB,cartilage matrix isdeficient insulfated proteoglycans. Wehavestudied cartilage extracts ofonenewborn withachondrogenesis type IBandfound that proteoglycans werequantitatively reduced, and, unlike incontrol cartilage, they didnotstain withtoluidine blue anddid notbind toDEAE.Impaired synthesis ofsulfated proteoglycans wasobserved also infibroblast cultures ofthe achondrogenesis IBpatient. Radioactive labeling andimmunoprecipitation studies indicated that coreprotein and side chains ofproteoglycans weresynthesized normally butwerenotsulfated. Analysis ofsulfate metabolism in fibroblast cultures showed, inthepatient's cells, normal intracellular levels offree sulfate butmarkedly reduced levels ofthetwointermediate compounds inthesulfate activation pathway, adenosine-phosphosulfate andphosphoadenosine-phosphosulfate. Theresults canbeexplained bydeficient activity ofoneoftheenzymes responsible forthebiologic activation ofsulfate, possibly similar tothat observed incartilage (but notinskin) oftherecessive, nonlethal mouse mutant brachymorphic andleading todefective sulfation ofmacromolecules. Expression of thesulfation defect incultured fibroblasts mayoffer adiagnostic tool forthedisorder.