Inherited disorders of glycoprotein synthesis: cell biological insights.

Disorders of glycoprotein synthesis have been described only recently, and few have been studied extensively at both the clinical and biochemical level. The identification and characterization of these rare diseases are important, not only for the patients and their families, but because they offer enormous insight into biological processes. For example, the targeting of acid hydrolases to lysosomes by mannose-6-phosphate was discovered as a direct result of the elucidation of the defect in I-cell disease. The notion of carbohydrates as targeting agents continues to have ramifications today, with the success of macrophage-targeted enzyme replacement therapy for Gaucher disease. Likewise, confirmation of the in vivo role of fucose-containing glycans and selectins in neutrophil function came from studies using specimens from patients with leucocyte adhesion deficiency type II due to reduced availability of GDP-fucose. Identification of the in vivo ligands of selectins also has implications for anti-inflammatory therapies. Macular corneal dystrophy and spondyloepiphyseal dysplasia tarda offer an opportunity to investigate the number of different sulfotransferases in cells, their substrates, and their tissue expression. The Ehlers-Danlos progeroid variant offers insight into the function and regulation of the proteoglycan decorin, and suggests that several of the enzymes involved in proteoglycan synthesis may function as a multienzyme complex. The common occurrence of hypergonadotropic hypogonadism in patients with galactosemia or carbohydrate-deficient glycoprotein protein syndrome, due to defective N-linked glycosylation, suggests that ovarian function is particularly dependent on proper glycan-synthesis. A host of other concepts await discovery as a fuller contingent of human disorders of glycan synthesis achieves recognition.