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Defects of N-linked glycosylation represent diseases with multiple organ involvements that are classified as congenital disorders of glycosylation (CDG). In recent years, several CDG types have been attributed to defects of dolichol-linked oligosaccharide assembly in the endoplasmic reticulum. The profiling of [ 3 H]mannose-labeled lipid-linked oligosaccharides was instrumental in identifying most of these glycosylation disorders. However, this method is poorly suited for the identification of short lipid-linked oligosaccharide biosynthesis defects. To adequately resolve deficiencies affecting the first steps of lipid-linked oligosaccharide formation, we have used a non-radioactive procedure employing the fluorescence detection of 2-aminobenzamide-coupled oligosaccharides after HPLC separation. By applying this method, we have detected the accumulation of dolichylpyrophosphate-GlcNAc 2  in a previously untyped CDG patient. The accumulation pattern suggested a deficiency of the  ALG1  β1,4 mannosyltransferase, which adds the first mannose residue to lipid-linked oligosaccharides. This was supported by the finding that this CDG patient was compound heterozygous for three mutations in the  ALG1  gene, leading to the amino acid substitutions S150R and D429E on one allele and S258L on the other. The detrimental effect of these mutations on  ALG1  protein function was demonstrated in a complementation assay using  alg1 Saccharomyces cerevisiae  yeast mutants. The  ALG1  mannosyltransferase defect described here represents a novel type of CDG, which should be referred to as CDG-Ik.

Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik