Deficiency of GDP-Man:GlcNAc2-PP-Dolichol Mannosyltransferase Causes Congenital Disorder of Glycosylation Type Ik
(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.
(Less)
- author
- Schwarz, Markus ; Thiel, Christian ; Lübbehusen, Jürgen ; Dorland, Bert ; De Koning, Tom LU ; Von Figura, Kurt ; Lehle, Ludwig and Körner, Christian
- publishing date
- 2004-01-01
- 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
- id
- 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}}, }