Perspectives on Glycosylation and Its Congenital Disorders

Abstract

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic disorders, expanded the knowledge of known disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen-host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions.

Keywords: Glycosylation; next-generation sequencing.

Figure 1. Discovery of glycosylation disorders

The distribution of glycosylation-related disorders by the year they were identified. They are grouped according to the glycosylation pathway which they affect and while most fall within a clear specific pathway, there are those that can affect multiple glycosylation disorders. This describes disorders identified up to the end of 2017. This figure is an updated version adapted from Freeze, H.H. et al. (2014) [10].

Figure 2, Key Figure. N-linked glycosylation pathway

A schematic of the N-linked pathway highlighting those genes required for the both the initial steps of lipid linked oligosaccharide synthesis as well as several key components for glycan processing within the Golgi. These genes highlighted in red represent known loci for glycosylation disorders. This figure is an updated version adapted from Freeze, H.H. et al. (2015) [4]