Glycoconjugate abnormalities in patients with congenital dyserythropoietic anaemia type I, II and III

Abstract

Summary. Congenital dyserythropoietic anaemia type II (CDA II) is well known for glycosylation abnormalities affecting erythrocyte membrane glycoconjugates that encompass hypoglycosylation of band 3 glycoprotein and accumulation of glycosphingolipids: lactotriaosylceramides, neolactotriaosylceramide and polyglycosylceramides. These abnormalities were not observed in erythrocytes from patients with CDA of either type I or III. Recently, however, we have described a CDA type I patient in Poland with identical, though less pronounced, glycoconjugate abnormalities to those observed in patients with CDA type II. The abnormalities included partial unglycosylation of O-linked glycosylation sites in glycophorin A. These abnormalities are now reported in three Bedouin patients from Israel with CDA type I. In addition, the erythrocyte membranes of these patients exhibited highly increased globotetraosylceramide content. Glycoconjugate abnormalities were also present in erythrocyte membranes from three patients from Northern Sweden with CDA type III but they almost exclusively affected glycosphingolipids. In erythrocytes of all patients examined including one with CDA type II, polyglycosylceramides were significantly hypoglycosylated although, on a molar basis, their contents in erythrocyte membranes were increased. Thus, glycoconjugate abnormalities of varying intensity occur in erythrocyte membranes from all patients with CDA that were investigated.

Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in theSEC23Bgene

“…It is a matter of debate if the impaired glycosylation is the primary cause of the disorder or a phenomenon secondary to other pathogenic mechanisms [Zdebska et al, 2001[Zdebska et al, , 2007. Recent studies on N-glycosylation of erythrocyte membrane proteins in CDAII patients indicate that CDAII is not a distinct glycosylation disorder but is caused by a defect disturbing Golgi processing in erythroblasts [Denecke et al, 2008]; however, the biochemical mechanism causing CDAII remains unknown and the aberrant gene has not so far been elucidated.…”

Abnormal Glycosylation of Red Cell Membrane Band 3 in the Congenital Disorder of Glycosylation Ig

“…We failed to observe any gross change in the mobility of glycophorin A in SDS-PAGE (not shown). This glycoprotein has normally about 12 O-linked glycans, as shown by its content of GalNAc (15). This number is preserved in glycophorin A of the patient ( Table 2).…”

“…In contrast, this glycoprotein is partly unglycosylated (nonglycosylated) in CDG Ia (9) and in several patients with CDA I and CDA II (15,29,30). In all these cases, glycosylation of band 3 was reduced.…”

“…Normal contents of most glycosphingolipids, including polyglycosylceramides, in red cells of the patient sharply separate CDG Ig from CDA I-III, because, in the latter group of diseases, lactotriaosylceramide, neotetraosylceramide, and polyglycosylceramides are invariably elevated (29,32,33). Polyglycosylceramides are, in addition, hypoglycosylated (29,34).…”

“…Normal contents of most glycosphingolipids, including polyglycosylceramides, in red cells of the patient sharply separate CDG Ig from CDA I-III, because, in the latter group of diseases, lactotriaosylceramide, neotetraosylceramide, and polyglycosylceramides are invariably elevated (29,32,33). Polyglycosylceramides are, in addition, hypoglycosylated (29,34). It has been proposed that the increased content of polyglycosylceramides in erythrocytes of CDA II patients is of a compensatory type because band 3 and polyglycosylceramides have glycans of the same polylactosamino type that are synthesized, presumably, by the same glycosyltransferases (for review, see Ref.…”