Congenital disorders involving defective N-glycosylation of proteins.

This review deals with several of the main autosomal recessive congenital disorders involving defective N-glycosylation of proteins (the addition of glycans linked to the polypeptide chain by a beta-linkage between the anomeric carbon of N-acetylglucosamine and the amido group of L-asparagine). These congenital disorders of glycosylation (CDG, previously known as carbohydrate-deficient glycoprotein syndromes) are a group of multisystemic diseases often involving severe psychomotor retardation. Six distinct variants of CDG in group I (types Ia-If) have been described to date and the defects have been localized to deficiencies in the assembly of the dolichylpyrophosphate-linked oligosaccharide N-glycan precursor and its transfer to asparagine residues on the nascent polypeptides. Two variants of CDG group II (types IIa and IIb) have been identified as defects in the processing of protein-bound N-glycans. Hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS; congenital dyserythropoietic anemia type II) presents as a relatively mild dyserythropoietic anemia. The genetic defect in most cases of HEMPAS is not known, but alpha-3/6-mannosidase II is involved in at least some patients. Leukocyte adhesion deficiency type II (LAD II) is a rare disorder characterized by recurrent infections, persistent leukocytosis and severe mental and growth retardation. LAD II is due to lack of availability of GDP-fucose. The study of these diseases and of relevant animal models has provided strong evidence that N-glycans are essential for normal mammalian development.