CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME - NOT AN N-LINKED OLIGOSACCHARIDE PROCESSING DEFECT, BUT AN ABNORMALITY IN LIPID-LINKED OLIGOSACCHARIDE BIOSYNTHESIS

The carbohydrate-deficient glycoprotein syndrome (CDGS) is a developme ntal disease associated with an abnormally high isoelectric point of s erum transferrin. Carbohydrate analyses of this glycoprotein initially suggested a defect in N-linked oligosaccharide processing, although m ore recent studies indicate a defect in the attachment of these sugar chains to the protein. We studied both serum glycoproteins and fibrobl ast-derived [2-H-3]mannose-labeled oligosaccharides from CDGS patients and normal controls. While there was a decrease in the glycosylation of serum glycoproteins of affected individuals, differences were not s een in either monosaccharide composition or oligosaccharide structures . The lectin-binding profiles of glycopeptides from [2-H-3]mannose-lab eled fibroblasts were likewise indistinguishable. However, the incorpo ration of [2-H-3]mannose into both glycoproteins and the dolichol-link ed oligosaccharide precursor was significantly reduced, Thus, at least in some patients, CDGS is not due to a defect in processing of N-link ed oligosaccharides, but rather to defective synthesis and transfer of nascent dolichol-linked oligosaccharide precursors. This abnormality could result in both a failure to glycosylate some sites on some prote ins, as well as secondary abnormalities in overall glycoprotein proces sing and/or function.