Copyright © 2004 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 74, Issue 3, 472-481, 1 March 2004
doi:10.1086/382492
Deficiency of GDP-Man:GlcNAc2-PP-Dolichol Mannosyltransferase Causes Congenital Disorder of Glycosylation Type Ik
Markus Schwarz2, *, Christian Thiel1, *, Jürgen Lübbehusen1, Bert Dorland3, Tom de Koning4, Kurt von Figura1, Ludwig Lehle2 and Christian Körner1, 
, 
1 Georg-August-Universität Göttingen, Biochemie II, Göttingen, Germany
2 Universität Regensburg, Lehrstuhl für Zellbiologie und Pflanzenphysiologie, Regensburg, Germany
3 UMC Utrecht, Department of Metabolic and Endocrine Diseases, Utrecht, The Netherlands
4 UMC Utrecht, Department of Pediatric Metabolic Diseases, Utrecht, The Netherlands
Address for correspondence and reprints: Dr. Christian Körner, Georg-August-Universität Göttingen, Biochemie II, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany* These authors contributed equally to this work.
Abstract
The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907). The disease belongs to the group of congenital disorders of glycosylation (CDG) and is designated as subtype CDG-Ik. In patient-derived serum, the total amount of the glycoprotein transferrin was reduced. Moreover, a partial loss of N-glycan chains was observed, a characteristic feature of CDG type I forms. Metabolic labeling with [6-3H]glucosamine revealed an accumulation of GlcNAc2-PP-dolichol and GlcNAc1-PP-dolichol in skin fibroblasts of the patient. Incubation of fibroblast extracts with [14C]GlcNAc2-PP-dolichol and GDP-mannose indicated a severely reduced activity of the β1,4-mannosyltransferase, elongating GlcNAc2-PP-dolichol to Man1GlcNAc2-PP-dolichol at the cytosolic side of the endoplasmic reticulum. Genetic analysis of the patient’s hALG1 gene identified a homozygous mutation leading to the exchange of a serine residue to leucine at position 258 in the hALG1 protein. The disease-causing nature of the hALG1 mutation for the glycosylation defect was verified by a retroviral complementation approach in patient-derived primary fibroblasts and was confirmed by the expression of wild-type and mutant hALG1 in the Saccharomyces cerevisiae alg1-1 strain.
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