Diseases of glycosylation beyond classical congenital disorders of glycosylation

Abstract

BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

“…Their number is steadily growing with some 50 CDG having been reported (Jaeken 2010(Jaeken , 2011Rafiq et al 2011;Saigoh et al 2011;Baasanjar et al 2011;Hennet 2012). Most of them are multisystem diseases, but skeletal abnormalities are an important/predominant clinical feature in only about 20 % of the known CDG.…”

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

“…These can be divided into the following major categories: disorders of protein N-glycosylation or O-glycosylation, disorders of lipid and glycosylphosphatidylinositol (GPI) anchor glycosylation and disorders of multiple glycosylation pathways (Freeze 2006;Hennet 2012), with variable symptomatic severity. Almost all organs are affected with a particular impact on nervous development, immune, hepatic and gastrointestinal systems (Freeze and Aebi 2005;Freeze et al 2015).…”

Deglycosylation systematically improves N-glycoprotein identification in liquid chromatography–tandem mass spectrometry proteomics for analysis of cell wall stress responses in Saccharomyces cerevisiae lacking Alg3p

“…4 Because of its importance in diverse biological systems, protein N-glycosylation is of general interest in proteomic identification and protein characterisation studies. Changes in glycosylation have been associated with a wide variety of conditions including inherited disease, cancer and infection [7,[16][17][18][19][20]. However, relatively specialized sample preparation, detection methods and data analysis outside the scope of many studies are often required for detailed glycosylation analysis [21,22].…”