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.