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Glycosylation is an important posttranslational protein modification occurring in the cytoplasm, the endoplasmic reticulum, and the Golgi apparatus. A rapidly growing family of genetic diseases is due to defects in protein glycosylation (congenital disorders of glycosylation [CDG]). Most CDG are severe, multisystem diseases with important neurological involvement. Some 30 CDG have been identified. CDG due to an N-glycosylation defect (there are 18 disorders) comprise two groups: CDG-I (with absence of one or more glycans; CDG-Ia through CDG-IL) and CDG-II (with incomplete glycans; CDG-IIa through CDG-IIf). Six disorders have been identified in O-glycosylation, including some long-known diseases such as hereditary multiple exostoses; another six disorders have a combined N- and O-glycosylation defect. Important tools in the diagnosis are transferrin isoelectric focusing, analysis of lipid-linked oligosaccharides and of protein-linked glycans, and mutation analysis.

Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases caused by defects in the synthesis of the glycan moiety of glycoconjugates (glycoproteins and glycolipids). There are two main types of protein glycosylation: N-glycosylation and O-glycosylation. N-glycosylation (N-glycans attached to an amino group of asparagine of proteins) comprises an assembly part and a processing part and extends over three cellular compartments: the cytosol, the endoplasmic reticulum (ER), and the Golgi.

The assembly part of the N-glycosylation starts on the cytosolic side of the ER, with the transfer of N-acetylglucosamine (GlcNAc) phosphate from UDP-GlcNAc to membrane-bound dolichyl monophosphate (Dol-P), forming GlcNAc-pyrophosphate-dolichol (GlcNAc-PP-Dol). One GlcNAc and five mannose (Man) residues are subsequently attached to this lipid-linked monosaccharide in a stepwise manner (Fig. 163-1). The donor of these mannoses is a nucleotide-activated sugar, GDP-Man, which is synthesized from fructose 6-phosphate, an intermediate of the glycolytic pathway (Fig. 163-2). The lipid-linked heptasaccharide Man5GlcNAc2 is translocated by a flippase across the ER membrane and is elongated at the lumenal side by the attachment of four mannose residues and subsequently of three glucose residues. The four mannosyltransferases and three glucosyltransferases involved require dolichyl-phosphate-bound monosaccharides (Dol-P-Man and Dol-P-Glc). The completed Glc3Man9GlcNAc2 oligosaccharide is then transferred to selected asparagine residues of the nascent proteins by the oligosaccharyltransferase complex.

Figure 163-1.

Scheme of the endoplasmic reticulum part of the N-glycosylation pathway (see text for explanation). The black bar beside ALG6 indicates the defect in CDG-Ic (ALG6 or glucosyltransferase I defect).

Figure 163-2.

Scheme of the synthesis of guanosine diphosphate (GDP)-mannose from fructose 6-phosphate. Vertical red bars indicate defects in CDG-Ia (PMM2 defect) and in CDG-Ib (PMI defect).

The processing part of the N-glycosylation starts in the ER by trimming the glucoses (catalyzed by glucosidases I and II) and one mannose (catalyzed by α-mannosidase I). The residual glycoprotein intermediate is directed to the cis-Golgi, where the processing pathway branches. A minor branch targets glycoproteins to the ...

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