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Congenital disorders of glycosylation (CDG) comprise a continuously growing group of monogenetic inherited diseases in glycoprotein biosynthesis1,2,3,4,5,6 (Figure 44-1) which affect the generation of structurally highly diverse oligosaccharides that are covalently attached to proteins mostly by N-glycosidic linkage to amino groups of asparagine residues, or by O-glycosidic linkage to hydroxyl groups of serine or threonine residues. The oligosaccharide moieties determine crucial biological processes like protein quality control, directed protein transport, enzymatic activity, and protein stability. Deficiencies in this complex metabolic pathway lead to multi-organ diseases with neurologic symptoms often dominating (see At-A-Glance). Based on the glycosylation pattern of serum transferrin in the isoelectric focusing and thereby corresponding to their subcellular localization, CDG have traditionally been subdivided in “CDG-I” and “CDG-II.” CDG-I comprise deficiencies that either diminish the biosynthesis of dolichol-linked oligosaccharides or reduce their transfer onto newly synthesized proteins by the oligosaccharyltransferase complex in the endoplasmic reticulum. CDG-II affect the subsequent trimming and elongation of glycans bound to proteins in the endoplasmic reticulum and Golgi apparatus (Figure 44-1). The identification of a considerable number of new CDG types afforded the improvement of nomenclature which now connect the abbreviation of defective proteins with the term CDG (eg, deficiency of the enzyme phosphomannomutase 2 [PMM2]), formerly known as CDG-Ia, changed to PMM2-CDG (see At-A-Glance). CDG of unknown molecular nature remain CDG-Ix or CDG-IIx. Here we focus on N-glycosylation defects including those which are combined with mucin-type O-glycosylation involvement, as deficiencies in O-mannosylation leading to muscular dystrophies with neurological impairment have recently been reviewed elsewhere.7,8

FIGURE 44-1.

Assembly and processing of N-linked glycans. The biosynthesis of N-linked glycans starts with the transfer of the nucleotide-activated sugars N-acetylglucosamine and mannose onto the lipid-carrier dolichol (LLO) at the outer leaflet of the endoplasmic reticulum up to an oligosaccharide with the structure Man5GlcNAc2-PP-dolichol. Following the transfer into the lumen of the endoplasmic reticulum by a flippase mechanism, the nascent glycan is further elongated with mannose and glucose residues, which are transferred from dolichol-phosphate-mannose and dolichol-phosphate-glucose donors at the luminal side of the endoplasmic reticulum. All elongation reactions inside and outside the endoplasmic reticulum are catalyzed by a subset of different glycosyltransferases. The oligosaccharide Glc3Man9GlcNaAc2 is transferred by the multisubunit enzyme complex oligosaccharyltransferase (OST) onto glycosylation consensus sequences of nascent proteins. After removal of the three glucose residues and one mannose residue, which plays a central part in protein folding quality control, the newly synthesized glycoprotein is transferred to the Golgi apparatus by vesicular transport. In the Golgi apparatus a series of trimming reactions lead to the shortened oligosaccharide structure GlcNAc2Man3. At this point a broad variety of N-acetylglucosamine transferases, galactosyltransferases, sialyltransferases, and fucosyltransferases can elongate the oligosaccharide to its mature form, resulting in a tremendous heterogeneity. Molecular defects in the glycoprotein biosynthesis are ...

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