Glycan-related genes and genetic disorders.

Abstract

Glycosylation is a ubiquitous and essential post-translational modification in biological systems. Most cell-surface and secreted proteins are glycosylated: the glycans contribute to the structural integrity of proteins and cell membranes, and are involved in numerous physiological functions from cell-cell communication and modulation of extracellular signals to immune response and tissue development. The vast array of N-linked, O-linked, and proteoglycan-type glycans are synthesized in a stepwise manner through the coordinated action of numerous glycosyltransferases and glycosidases encoded by "glycogenes". At present, more than 400 glycogenes are involved in glycan biosynthesis in humans. Given the essential roles of glycosylation, it is not surprising that mutations in glycogenes cause various genetic disorders, collectively referred to as congenital disorders of glycosylation (CDGs). However, directly linking specific gene mutations to altered glycan structures and resulting clinical symptoms remains a significant challenge because the biological functions are mediated not by the enzymes themselves, but by the diverse glycan structures that they generate. Many undiagnosed rare diseases are suspected to result from defects in genes involved in glycosylation pathways. Furthermore, reports of newly identified types of CDGs are steadily increasing. Comprehensive understanding of these disorders requires a multidisciplinary approach integrating genetics, biochemistry, glycomics, and clinical research. In this review, we first describe glycans, including the different types and their biological functions. Next, all of the glycogenes involved in various synthetic pathways are presented, followed by examples of genetic disorders caused by their mutation and the glycogenomic approaches used to explore them.