Human Molecular Genetics Advance Access published online on January 6, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh050
© 2004 by Oxford University Press
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1 Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
* To whom correspondence should be addressed. E-mail: thennet{at}access.unizh.ch.
Defects of N-linked glycosylation represent diseases with multiple organ involvements that are classified as congenital disorders of glycosylation (CDG). In the last years, several CDG types have been attributed to defects of dolichol-linked oligosaccharide assembly in the endoplasmic reticulum. The profiling of [3H]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 lipid-linked oligosaccharides after HPLC separation. By applying this method, we have detected the accumulation of dolichylpyrophosphate-GlcNAc2 in a previously untyped CDG patient. The accumulation pattern suggested a deficiency of the ALG1
Article
Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik
2 Institute of Microbiology, Swiss Federal Institute of Technology, Schmelzbergstrasse 7, 8092 Zürich, Switzerland
3 Center for Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium
4 Department of General Pediatrics, University Children's Hospital, University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
5 Institute of Physiology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Abstract 
1,4 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.
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