Deficiency of GDP-Man:GlcNAc2-PP-Dolichol Mannosyltransferase Causes Congenital Disorder of Glycosylation Type Ik

Research output: Contribution to journalArticle


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- 3H]glucosamine revealed an accumulation of GlcNAc 2-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.


  • Markus Schwarz
  • Christian Thiel
  • Jürgen Lübbehusen
  • Bert Dorland
  • Tom De Koning
  • Kurt Von Figura
  • Ludwig Lehle
  • Christian Körner
External organisations
  • University of Regensburg
  • University of Göttingen
  • University Medical Center Utrecht
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Other Basic Medicine
Original languageEnglish
Pages (from-to)472-481
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - 2004 Jan 1
Publication categoryResearch
Externally publishedYes