Carbohydrate-deficient Glycoprotein Syndrome: Not an N-linked Oligosaccharide Processing Defect, But an Abnormality in Lipid-linked Oligosaccharide Biosynthesis?

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The carbohydrate-deficient glycoprotein syndrome (CDGS) is a developmental disease associated with an abnormally high isoelectric point of serum transferrin. Carbohydrate analyses of this glycoprotein initially suggested a defect in N-linked oligosaccharide processing, although more recent studies indicate a defect in the attachment of these sugar chains to the protein. We studied both serum glycoproteins and fibroblast-derived (2-Hydrogen-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 seen in either monosaccharide composition or oligosaccharide structures. The lectin-binding profiles of glycopeptides from (2-Hydrogen-3)mannose-labeled fibroblasts were likewise indistinguishable. However, the incorporation of (2-Hydrogen-3)mannose into both glycoproteins and the dolichol-linked oligosaccharide precursor was significantly reduced. Thus, at least in some patients, CDGS is not due to a defect in processing of N-linked 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 proteins, as well as secondary abnormalities in overall glycoprotein processing and/or function. (J. Clin. Invest. 1994. 94:1901-1909.) Key words: mental retardation. serum glycoproteins. transferrin. dolichol. lipid-linked oligosaccharide

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