Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik

Markus Schwarz, Christian Thiel, Jürgen Lübbehusen, Bert Dorland, Tom de Koning, Kurt von Figura, Ludwig Lehle, Christian Körner

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The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-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-(3)H]glucosamine revealed an accumulation of GlcNAc(2)-PP-dolichol and GlcNAc(1)-PP-dolichol in skin fibroblasts of the patient. Incubation of fibroblast extracts with [(14)C]GlcNAc(2)-PP-dolichol and GDP-mannose indicated a severely reduced activity of the beta 1,4-mannosyltransferase, elongating GlcNAc(2)-PP-dolichol to Man(1)GlcNAc(2)-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.

Original languageEnglish
Pages (from-to)472-481
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - Mar-2004
Externally publishedYes


  • DNA Mutational Analysis
  • Genetic Diseases, Inborn
  • Glycosylation
  • Humans
  • Mannosyltransferases
  • Mutation, Missense
  • Oligosaccharides
  • Saccharomyces cerevisiae
  • Transferrin
  • Journal Article
  • Research Support, Non-U.S. Gov't

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