Receptor-mediated selective impairment of insulin-like growth factor-1 activity in congenital disorders of glycosylation patients.

ABSTRACT

BACKGROUND: Congenital disorders of glycosylation (CDG) patients share a basic feature of protein hypoglycosylation. Activity of growth factors and their receptors, glycoproteins playing a pivotal role during child development, remains unexplored in CDG patients. METHODS: Peripheral blood lymphocytes (PBL) isolated from 9 CDG patients and 12 healthy controls were cultured in the presence of fetal bovine serum (FBS), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1), and BrdU incorporation was measured. Levels of plasma IGF-1 and PBL IGF-1 receptor (IGF-1R) and its glycosylation were detected using immunoassay and western blot. RESULTS: CDG patients showed significantly less (P < 0.01) serum-induced 5'-Bromo-2'-deoxyuridine (BrdU) incorporation in PBL than in controls. PDGF-/FGF-stimulated BrdU incorporation showed no difference in patients and controls, whereas IGF-1-induced DNA synthesis was significantly (P < 0.01) less in patients. Plasma IGF-1 levels and PBL IGF-1 receptor protein were significantly (P < 0.01) reduced in patients as compared to controls. IGF-1 receptor in PBL of all CDG patients had significantly (P < 0.01) reduced carbohydrate content when compared with control. CONCLUSIONS: These results show selective impairment of IGF-1-induced DNA synthesis in lymphocytes of CDG patients through decreased gene expression and hypoglycosylation of the IGF-1 receptor.