All Congenital Disorders of Glycosylation (CDG) are associated in some way with changes in glycosylation, such as defective or reduced glycosylation. This makes Glycan Analysis the most promising method for screening CDGs. At CD BioGlyco, we have developed an advanced Glycomics Platform, providing glycan isolation, purification, and characterization services for our clients.
Glycosylation disease is a rare genetic disorder commonly referred to as CDG. CDG clinically manifests psychomotor retardation, developmental delay, coagulopathy, dysmorphic features, seizures, and stroke-like seizures. Defects affect the glycosylation pathway in nucleotide-sugar biosynthesis, nucleotide-sugar transporters, Glycosyltransferases, and vesicular transport, leading to structural changes in many classes of glycoconjugates. CDG can be divided into four groups, including N-Glycosylation Defects, O-glycosylation defects, lipid and glycosylphosphatidylinositol (GPI)-anchored glycosylation defects, and defects affecting multiple glycosylation pathways. Most CDGs known to date are defective in N-glycosylation. Classical barriers to N-glycosylation are 14 lipid-linked oligosaccharides (LLO) assembly defects in the endoplasmic reticulum (ER) and 2 processing defects in the Golgi apparatus.
N-Glycosylation is a major post-translational modification that occurs in the secretory pathway and is highly conserved in eukaryotes. N-Glycans play key roles in protein folding, transport, and signal transduction, and are involved in the occurrence and development of various diseases. N-Glycosylation is divided into the following four steps: 1) Assembly of lipid-linked oligosaccharide (LLO) precursor Glc3Man9GlcNAc2; 2) Oligosaccharyltransferase (OST) catalyzes the transfer of LLO precursors to nascent proteins; 3) Quality control process of glycoproteins;4) Further processing of N-glycans in the Golgi apparatus and conversion to mature forms. Here, we focus on disorders of N-glycans transfer during N-glycosylation.
ig.1 N-Glycosylation in the ER. (Hennet, 2012)
Following the Synthesis of intact N-glycan precursors, LLO is "bulk" transferred from its PP-dolichol (Dol) linked state to the asparagine (Asn) glycosylation site in the nascent protein. This process is catalyzed by the multi-subunit protein complex OST or dolichol-diphosphooligosaccharide: protein glycosyltransferase (DDOST) in the endoplasmic reticulum (ER). Mammalian cells express two OST complexes: OSTA and OSTB, of which STT3A and STT3B are catalytic subunits, respectively. Although human OSTA and OSTB show a high degree of structural similarity, there are two significant differences: 1) Due to differences in the surface of the protein that specifically interacts with either the OSTA-specific DC2 subunit or the OSTB-specific MAGT1 subunit, the specific interaction of OSTA but not OSTB with the transporter is possible; 2) The C-terminus of riboprotein I in human OSTA forms four helices on the cytoplasmic side, the feature that allows OSTA to interact with ribosomes. In short, OSTA's unique interactions with transporter and ribosomes enable the co-translational transport of fully assembled N-glycans to nascent proteins. OSTB transfers fully assembled N-glycans and incomplete N-glycans lacking three glucose (Glc) residues in a co- and post-translational manner.
Fig.2 Subunit composition of STT3A-OST and STT3B-OST. (Hennet, 2012)
Defects in any step required for LLO assembly in the ER produce structurally incomplete LLOs. But OST prefers intact LLO, which leads to hypoglycosylation of multiple glycoproteins. In addition, mutations in the OST subunit can also lead to CDG. STT3A and STT3B are part of two different OST complexes. The study found that patients with defects in either subunit of STT3A or STT3B have a typical multisystem phenotype. Transferrin glycosylation depends on the OST complex containing STT3A. Thus, transferrin glycosylation is abnormal in STT3A-CDG patients whereas transferrin glycosylation is normal in STT3B-CDG patients. MAGT1 is a subunit specific to OSTB. Abnormal transferrin glycosylation in MAGT1-CDG manifests as primary immunodeficiency characterized by chronic infection with Epstein-Barr virus (EBV).
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