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

Schwarz, Markus ; Thiel, Christian ; Lübbehusen, Jürgen ; Dorland, Bert ; De Koning, Tom LU ; Von Figura, Kurt ; Lehle, Ludwig and Körner, Christian (2004) In American Journal of Human Genetics 74(3). p.472-481
Abstract

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.... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Human Genetics
volume
74
issue
3
pages
10 pages
publisher
Cell Press
external identifiers
  • pmid:14973778
  • scopus:1542374061
ISSN
0002-9297
DOI
10.1086/382492
language
English
LU publication?
no
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7a3d272b-c416-4c67-a892-00df62379869
date added to LUP
2020-03-03 19:07:40
date last changed
2024-06-12 11:23:21
@article{7a3d272b-c416-4c67-a892-00df62379869,
  abstract     = {{<p>The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc <sub>2</sub>-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- <sup>3</sup>H]glucosamine revealed an accumulation of GlcNAc <sub>2</sub>-PP-dolichol and GlcNAc<sub>1</sub>-PP-dolichol in skin fibroblasts of the patient. Incubation of fibroblast extracts with [ <sup>14</sup>C]GlcNAc<sub>2</sub>-PP-dolichol and GDP-mannose indicated a severely reduced activity of the β1,4-mannosyltransferase, elongating GlcNAc<sub>2</sub>-PP-dolichol to Man<sub>1</sub>GlcNAc<sub>2</sub>-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.</p>}},
  author       = {{Schwarz, Markus and Thiel, Christian and Lübbehusen, Jürgen and Dorland, Bert and De Koning, Tom and Von Figura, Kurt and Lehle, Ludwig and Körner, Christian}},
  issn         = {{0002-9297}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{3}},
  pages        = {{472--481}},
  publisher    = {{Cell Press}},
  series       = {{American Journal of Human Genetics}},
  title        = {{Deficiency of GDP-Man:GlcNAc<sub>2</sub>-PP-Dolichol Mannosyltransferase Causes Congenital Disorder of Glycosylation Type Ik}},
  url          = {{http://dx.doi.org/10.1086/382492}},
  doi          = {{10.1086/382492}},
  volume       = {{74}},
  year         = {{2004}},
}