8 Congenital dyserythropoietic anaemia type II (HEMPAS) and its molecular basis

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Congenital dyserythropoietic anaemia type II (CDA II) is a rare genetic anaemia in humans, inherited in an autosomally recessive mode. CDA II is also called HEMPAS as this disease is characterized by hereditary erythroblastic multinuclearity with positive acidified serum lysis test. Analyses of CDA II erythrocyte membranes showed that the band 3 glycoprotein is underglycosylated. An aberrant glycosylation pattern is seen in the polylactosamine carbohydrates which are normally attached to the band 3 and band 4.5 glycoproteins. The polylactosamines are, however, accumulated in the form of glycolipids. Therefore a genetic factor in CDA II appears to block the glycosylation of protein acceptors and shift these carbohydrates to the lipid acceptors. Structural analysis of CDA II band 3 carbohydrates identified truncated hybrid-type oligosaccharides and suggests that the Golgi glycosylation enzyme(s), alpha-mannosidase II or N-acetylglycosaminyltransferase II is defective in CDA II. By using a cDNA probe for alpha-mannosidase II, one CDA II case has been identified as being defective in the gene encoding alpha-mannosidase II. At present, it is not clear whether CDA II is a genetically heterogenous collection of glycosylation deficiencies, or genetically homogenous but apparently heterogenous in phenotype expression. Freeze-fracture electron microscopy and immunoelectron microscopy revealed that the band 3 glycoproteins are clustered in CDA II erythrocyte membranes. The abnormal distribution of band 3 might cause an unstable membrane organization. In CDA II erythroblasts, the membrane proteins might also be underglycosylated and abnormally distributed. When normal erythroblasts were cultured in vitro in the presence of swainsonine (alpha-mannosidase inhibitor) the erythroblasts became multinucleared. It is, therefore, quite possible that the enzymic defect of alpha-mannosidase II could cause various morphological anomalies including multinuclearity. Because the genes encoding glycosylation enzymes are housekeeping genes, the enzyme defect of CDA II is not restricted to erythroid cells and there is also an abnormal glycosylation of hepatocyte glycoproteins. On the other hand, there are many types of cells and tissues which appear not to be affected by the CDA II defect. A mechanism for the erythroid-specific manifestation of CDA II and its tissue specificity are also discussed.