Abnormal Metabolism of Mannose in Families with Carbohydrate-Deficient Glycoprotein Syndrome Type 1

Abstract

Patients with carbohydrate-deficient glycoprotein syndrome (CDGS) Type 1 underglycosylate many glycoproteins by failing to add entire N-linked carbohydrate chains to them. The primary defect in these patients has been reported as a >90% deficiency in phosphomannomutase activity (PMM), the enzyme that converts mannose-6-phosphate to mannose-1-phosphate. This lesion reduces both the amount and the size of the lipid-linked oligosaccharide precursor. We have now analyzed the activity of PMM and the level of glycosylation in cultured fibroblasts as well as the level of blood mannose in seven CDGS Type 1 patients and their parents. All of these patients were ∼95% deficient in PMM activity and their parents had an average of 51% of control PMM activity. Furthermore, parental fibroblasts showed reduced glycosylation and a higher proportion of truncated N-linked chains compared to those made by control fibroblasts. Addition of 0.25 mmmannose to the culture medium corrected both the underglycosylation and size of the oligosaccharide chains in CDGS Type 1 patients and their parents. Finally, serum from CDGS patients had considerably reduced mannose levels (5–40 μm) compared to normal controls (40–80 μm) and some parents were below normal (16–103 μm). These results suggest that the reduced blood mannose level is a consequence of the PMM deficiency. This is the first inherited disorder in human metabolism that shows a decrease in available mannose. Increasing blood mannose levels might correct some protein underglycosylation in these patients.