CDGS Type II

Fig. 4.5.3 IEF patterns of serum transferrin. Sera from a control (lane 1), three CDG-I (CDG-Ia, CDG-Ic and CDG-Id lanes 2-4) and three CDG-II patients (CDG- , CDG-IId and CDG-IIx lanes 5-7) were analysed by IEF. In case of a control person, the main form of the protein carries four negatively charged sialic acid residues, even though small amounts of penta- and trisialo-transferrin are detectable. Additional disialo- and asialotransferrin forms indicate CDG-type I (left side). In some cases of CDG type II, additional trisialo- and monosialotransferrin forms may occur, which are due to the loss of either one or three sialic acid residues (right side). Isoforms of transferrin that are independent of a pathological phenotype and that cause double bands in IEF are visible in lanes 4 and 6. CDG-IIx indicates a transferrin pattern that is caused by a so far unknown molecular defect from the CDG-II type...

CDG-type II syndrome [265,268] is a separate variant since it is characterized by a severe decrease in the activity of A-acetylglucosaminyltransferase II (UDP-GlcNAc a6-D-mannoside (3-l,2-A-acetylglucosaminyltransferase). As a consequence, the serotransferrin isoforms contain two truncated monoantennary glycans of which the primary structures are described in Fig. 19. 

Fig. 19. Primary structure of the glycan from human serotransferrin isolated from a patient with carbohydrate-deficient syndrome (CDG) type II [265,268], R, GIcNAc(pi-4)GIcNAc(pi-N)Asn.

So far only two patients have been reported as CDGS type II [16]. Both patients showed coarse facial features, low-set ears, widely spaced nipples, ventricular septal defects, generalized hypotonia and limb weakness. They had a severe psychomotor retardation but no peripheral neuropathy and a normal cerebellum on nuclear magnetic resonance imaging. 

Indeed, GnT-II activity was greatly reduced in fibroblast extracts from CDGS type II patients [16]. Direct sequence of GnT-II coding region from CDGS type II patients identified point mutations on the catalytic domain of GnT-II [17]. These mutation were inherited consistently with CDGS type II phenotypes, cause cell extracts expressing these mutant GnT-II proteins, which have the same missense... 

Type II disorders are due to mutations in genes encoding enzymes (eg, GIcNAc transferase-2, causing CDG lla) involved in the processing of N-glycan chains... 

Metabolic labelling is carried out in primary skin fibroblasts. It is helpful to have an internal control from a CDG-type I patient with an early N-glycosylation deficiency like CDG-Ii or CDG-Ik. 

In all known types of CDG-I it has been observed that due to the loss of sialic acid residues, in addition to tetrasialo-transferrin, more or less pronounced di- and asialo-transferrin bands appear, which are evoked by the loss of either one or both complete oligosaccharide chains (Fig. 4.5.3, lanes 2-4). In contrast to CDG-I, changes in the charge of serum transferrin of most known CDG-II types are due to shortening of the oligosaccharide moieties (Fig. 4.5.3, lanes 5-7). 

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