In the early 1980s, the first congenital disease of glycosylation (CDG) patient with Defective N-Protein Glycosylation was discovered. Such patients often present with neurological deficits, such as developmental delay and growth failure. CDG is difficult to diagnose clinically. Glycan Profiling and Glycan Structure Analysis are useful laboratory aids for CDG. The main cause of the disease is mutations or deletions of Glycosyltransferases and glycosidases in the N-glycosylation process. Below we will introduce several enzymes involved in N-linked glycosylation disorders.
OST is a membrane protein complex that transfers the lipid-linked oligosaccharide (LLO) precursor (Dol-PP-GlcNAc2Man9Glc3) from dolichol (Dol) to nascent proteins. The OST complex contains at least seven subunits (STT3A/STT3B, RPN1, RPN2, OST48/DDOST, OST4, TMEM258, and DAD1). Mutations in these genes have been identified in a small number of cases of nonsyndromic mental retardation.
In the endoplasmic reticulum (ER), glucosidase I and glucosidase II remove glucose (Glc) residues from transferred LLO precursors. Currently, patients with glucosidase I deficiency have been reported. Abnormal N-glycan pruning results in deformity, hypotonia, and even death in patients.
Mannosidase I is responsible for the removal of mannose (Man) residues on properly folded proteoglycans in the ER to generate GlcNAc2Man8. Afterward, the folded glycoprotein exits the ER into the Golgi apparatus. Twelve patients with ER mannosidase I deficiency who presented with speech delay and mild dysmorphia have been described.
Fig.1 N-Glycans are schematically represented with the enzymes known to be associated with CDG. (Hennet, 2012)
Gal is added to the N-acetylglucosamine (GlcNAc) residues of the core glycan structure under the catalysis of β1-4 or β1-3 Gal transferase. A defect in β1-4 Gal-transferase-1 (B4GALT1) that elongates the core structure has been reported. The patient is due to the translation of a truncated B4GALT1 protein caused by a single base insertion.
GlcNAc transferase II (GnT-II, MGAT2) transfers GlcNAc residues from the UDP-GlcNAc to newly exposed Man in the Golgi, generating a common core structure of complex glycans (GlcNAc2Man5GlcNAc2). When MGAT2 is abnormal, it leads to severe glycosylation disease, which is clinically manifested as severe psychomotor retardation, facial dysmorphic features, osteopenia and seizures.
Negatively charged sialic acid (Sia) is usually located at the terminal position of the glycan chain and is added by α2-3 or α2-6-sialyltransferase. Mutations in the α2-3 sialyltransferase gene (ST3GAL3) have been reported to affect brain glycoproteins, resulting in nonsyndromic mental retardation.
The N-linked glycosylation is carried out in the ER and the Golgi apparatus, and is mainly divided into three parts: 1) The synthesis of the LLO precursor composed of 14 sugar residues in the ER; 2) The overall transfer of the LLO precursor to nascent proteins; 3) Complex N-glycans generated by LLO processing in ER and Golgi apparatus. These steps are tightly controlled by many factors, and different N-glycan structures are synthesized in a cell-type, protein, and even glycosylation site-specific manner. Abnormalities in the glycosylation process can lead to corresponding glycosylation diseases. We introduce CDGs triggered by disorders in these three processes.
Glycosylation plays an important role in living organisms. CD BioGlyco is a leading glycosylation service provider and has developed advanced Glycomics and Glycoproteomics platforms to help clients solve serious difficulties and problems in glycosylation. If you have any glycosylation analysis needs, please feel free to contact us.
Reference:
