Chapter 74

## Abstract

This review is on genetic defects of N-glycan synthesis (CDGS; MIM 212065).
1. Many proteins undergo posttranslational modifications. Most membrane proteins and most extracellular proteins as well as several intracellular proteins, like lysosomal enzymes, are glycosylated. The structures of these oligosaccharides or glycans present on proteins are basically of two types defined by their linkage to the protein: O linked and N linked. N-linked glycans are bound to the amide group of asparagine via an N-acetylglucosamine residue. The biosynthetic pathway for the assembly of these N-glycans involves numerous glycosyltransferases that sequentially attach monosaccharides to the growing glycan unit using nucleotide-linked sugars or dolichol phosphate-linked sugars as donors. Subsequently a series of glycosidases and Golgi glycosyltransferases intervene in the further processing of the glycan moiety. The glycan units of glycoproteins serve a great number of diverse functions particularly in relation to the function and metabolism of the underlying proteins.

2. Type-I CDG syndromes have a type-I serum sialotransferrin pattern on isoelectrofocusing (IEF) characterized by increased di- and asialotransferrin bands. They are mostly due to defects in the N-glycan synthesis in the cytosol or in the endoplasmic reticulum (ER); some may be due to an N-glycan processing defect in the Golgi apparatus. Two pre-ER defects have been well characterized: phosphomannomutase (PMM) deficiency (carbohydrate-deficient glycoconjugate syndromes (CDGS) type IA) and phosphomannose isomerase (PMI) deficiency (CDGS type IB) Evidence has been presented in one family for deficient glucosylation of the dolichol-oligosaccharide ER intermediate.

Type-II CDG syndromes have a type-II serum sialotransferrin pattern on IEF, i.e., besides increased di- and asialotransferrin bands there is also an increase of the tri- and/or monosialotransferrin bands. They are probably all due to defects of the N-linked glycan processing in the Golgi apparatus. Only one defect has been identified: N-acetylglucosaminyltransferase (GnT) II deficiency (CDGS type IIA).

3. PMM (EC 5.4.2.28) deficiency (CDGS type IA) results in an autosomal recessive disease reported in at least 124 patients. It is a multisystem disease including specific dysmorphy in most patients and moderate to severe nervous system involvement. It is caused by mutations in the PMM2 gene (MIM 601785) on chromosome 16p13.

PMI (EC 5.3.1.8) deficiency (CDGS type IB) results in an autosomal recessive disease and has been reported in six patients belonging to four families. Two of them suffered from severe protein-losing enteropathy and three others (siblings) from recurrent vomiting. These five patients also had liver fibrosis. One patient had only transient liver disease. Oral mannose, given to one patient with protein-losing enteropathy, had a strikingly beneficial effect. The patient who showed only liver disease recovered completely after the introduction of solid food without extra mannose. In two patients, mutations were found in the PMI gene (MIM 602579) located on chromosome 15q22.

Deficient glucosylation of the dolichol-oligosaccharide intermediate in the ER was found in five members of an inbred family with mild to moderate psychomotor retardation and epilepsy. The basic defect is most probably in an ER-localized glucosyltransferase or in the synthesis of dolichyl-phosphoglucose.

GnT II (EC 2.4.1.143) deficiency (CDGS type IIA) is an autosomal recessive disease. The two reported patients had craniofacial dysmorphy and severe encephalopathy. They were homozygous for different point mutations of the GnT II gene that is located on chromosome 14q21.

Leukocyte adhesion deficiency syndrome type II is probably an autosomal recessive disease and has been described in two unrelated patients who suffered from recurrent bacterial infections without pus formation and showed typical facial features, short stature, and an encephalopathy. This phenotype appears to result from a general deficiency of fucose (N-glycans as well as O-glycans contain fucose) possibly due to a defect in the transformation of guanosine diphosphomannose (GDP-mannose) into GDP-fucose.

4. A number of patients with an unexplained N-glycosylation defect have been reported or are known to the authors. The majority of them have a type-I serum sialotransferrin pattern; it is proposed to name these CDGS type I-X for the time being. Some of these patients have only a mild nervous system involvement. Studies are under way to unravel the basic defects in these patients.

5. Deficient N-glycosylation has been demonstrated in two well-known genetic diseases of carbohydrate metabolism: galactosemia and hereditary fructose intolerance. The hypoglycosylation in galactosemia is possibly due, at least in part, to a disturbed transport of uridine diphosphogalactose into the Golgi; in hereditary fructose intolerance, it is secondary to inhibition of PMI by the accumulated fructose 1-phosphate.

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