Congenital Disorder of Glycosylation (CDG) - Ih

Abstract

Congenital Disorders of Glycosylation (CDG) comprise a rapidly growing group of multisystemic inherited disorders caused by mutations in genes which are required for the biosynthesis of glycoproteins. Here the molecular defect in a new type of CDG with an unusual clinical phenotype and a difficult way of detection is described. The disorder was localised in the decreased activity of the human ortholog of the yeast ALG2 mannosyltransferase which catalyses the transfer of mannose residues onto Man1GlcNAc2-PP-dolichyl at the cytosolic site of the endoplasmic reticulum in the early onset of glycoprotein biosynthesis. The patient presented normal at birth but developed by the time a multisystemic disorder with mental retardation, myelinisation defects, seizures, coloboma of the iris, hepatomegaly and coagulation abnormalities. Isoelectric focussing of serum transferrin indicated a partial loss of complete N-glycan side chains, which was comparable to classical CDG-Ia patients. Analysis of ALG2-mannosyltransferase in skin fibroblasts of the patient showed a severely reduced activity which leads to the accumulation of Man1GlcNAc2-PP-dolichol and Man2GlcNAc2-PP-dolichol.Genetic analysis of the alg2 mannosyltransferase cDNA revealed a deletion mutation which led to premature translation stop and loss of the C-terminal 45 amino acids. The patient was homozygous for this mutation at the level of mRNA and heterozygous at the genomic level, which is probably due to the instability of one paternal allele. Retroviral gene transfer of the wildtype alg2-cDNA into patient derived fibroblasts normalized the mannosyltransferase activity.