O-glycosylation disorders pave the road for understanding the complex human O-glycosylation machinery

Abstract

Over 100 human Congenital Disorders of Glycosylation (CDG) have been described. Of these, about 30% reside in the O-glycosylation pathway. O-glycosylation disorders are characterized by a high phenotypic variability, reflecting the large diversity of O-glycan structures. In contrast to N-glycosylation disorders, a generic biochemical screening test is lacking, which limits the identification of novel O-glycosylation disorders. The emergence of next generation sequencing (NGS) and O-glycoproteomics technologies have changed this situation, resulting in significant progress to link disease phenotypes with underlying biochemical mechanisms. Here, we review the current knowledge on O-glycosylation disorders, and discuss the biochemical lessons that we can learn on 1) novel glycosyltransferases and metabolic pathways, 2) tissue-specific O-glycosylation mechanisms, 3) O-glycosylation targets and 4) structure-function relationships. Additionally, we provide an outlook on how genetic disorders, O-glycoproteomics and biochemical methods can be combined to answer fundamental questions regarding O-glycan synthesis, structure and function.