Mechanisms in Protein O-Glycan Biosynthesis and Clinical and Molecular Aspects of Protein O-Glycan Biosynthesis Defects: A Review

Genetic diseases that affect the biosynthesis of protein O-glycans are a rapidly growing group of disorders. Because this group of disorders does not have a collective name, it is difficult to get an overview of O-glycosylation in relation to human health and disease. Many patients with an unsolved defect in N-glycosylation are found to have an abnormal O-glycosylation as well. It is becoming increasingly evident that the primary defect of these disorders is not necessarily localized in one of the glycan-specific transferases, but can likewise be found in the biosynthesis of nucleotide sugars, their transport to the endoplasmic reticulum (ER)/Golgi, and in Golgi trafficking. Already, disorders in O-glycan biosynthesis form a substantial group of genetic diseases. In view of the number of genes involved in O-glycosylation processes and the increasing scientific interest in congenital disorders of glycosylation, it is expected that the number of identified diseases in this group will grow rapidly over the coming years. We first discuss the biosynthesis of protein O-glycans from their building blocks to their secretion from the Golgi. Subsequently, we review 24 different genetic disorders in O-glycosylation and 10 different genetic disorders that affect both N- and O-glycosylation. The key clinical, metabolic, chemical, diagnostic, and genetic features are described. Additionally, we describe methods that can be used in clinical laboratory screening for protein O-glycosylation biosynthesis defects and their pitfalls. Finally, we introduce existing methods that might be useful for unraveling O-glycosylation defects in the future.