Human Molecular Genetics Advance Access originally published online on January 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 5 535-542
DOI: 10.1093/hmg/ddh050
Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik
1Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland, 2Institute of Microbiology, Swiss Federal Institute of Technology, Schmelzbergstrasse 7, 8092 Zürich, Switzerland, 3Center for Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium and 4Department of General Pediatrics, University Children's Hospital, University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Received October 29, 2003; Revised December 15, 2003; Accepted December 22, 2003
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 [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 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 ß1,4 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.
* To whom correspondence should be addressed at: Institute of Physiology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Tel: +41 16355080; Fax: +41 16356814; Email: thennet{at}access.unizh.ch
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