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 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 [2-3H]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 [2-3H]-mannose-labeled fibroblasts were likewise indistinguishable. However, the incorporation of [2-3H]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.
Powell
L D
LD
Glycobiology Program, University of California at San Diego Cancer Center, La Jolla 92093.
Paneerselvam
K
K
Vij
R
R
Diaz
S
S
Manzi
A
A
Buist
N
N
Freeze
H
H
Varki
A
A
D001798:Blood Proteins / Q000032:analysis; D002241:Carbohydrates / Q000032:analysis*; D002460:Cell Line; D005260:Female; D006023:Glycoproteins / Q000032:analysis / Q000097:blood*; D006031:Glycosylation; D006801:Humans; D007525:Isoelectric Focusing; D050356:Lipid Metabolism; D008358:Mannose / Q000378:metabolism; D009844:Oligosaccharides / Q000096:biosynthesis*; D013577:Syndrome; D014168:Transferrin / Q000737:chemistry*
D001798:Blood Proteins; D002241:Carbohydrates; D006023:Glycoproteins; D009844:Oligosaccharides; D014168:Transferrin; D008358:Mannose