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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 and lipid glycosylation (congenital disorders of glycosylation [CDG]). Most CDGs are severe, multisystem diseases with prominent neurologic involvement. Nearly 100 CDGs have been identified. This chapter is limited to the protein glycosylation defects (some 80 disorders). Twenty-five CDGs are due to an N-glycosylation defect (Table 158-1). Twenty disorders have been identified in O-glycosylation, including some long-known diseases such as hereditary multiple exostoses (Table 158-2). Thirty-four disorders have a combined N- and O-glycosylation defect, including dolichol metabolism defects (Table 158-3). Important tools in the diagnosis are serum transferrin (Tf) isoelectric focusing (IEF), serum apolipoprotein C-III (apo C-III) isoelectrofocusing, protein-linked glycan analysis, and genetic analysis. In this text, we use the nomenclature introduced in 2009, namely the official gene symbol (not in italics) followed by “-CDG.”


CDGs 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 2 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 3 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 5 mannose (Man) residues are subsequently attached to this lipid-linked monosaccharide in a stepwise manner (Fig. 158-1). 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. 158-2). 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 4 mannose residues and subsequently of 3 glucose residues. The 3 mannosyltransferases and 3 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 158-1

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

Figure 158-2

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

The processing part of the N-glycosylation ...

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