Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

Abstract

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.

• Authors: T Imbach, B Schenk, E Schollen, P Burda, A Stutz, S Grunewald, N M Bailie, M D King, J Jaeken, G Matthijs, E G Berger, M Aebi, T Hennet
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 105 Issue 2 Pg. 233-9 (Jan 2000) ISSN: 0021-9738 [Print] United States
• PMID: 10642602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD59 Antigens
• Carrier Proteins
• Fungal Proteins
• Isoenzymes
• Lipocalins
• Membrane Proteins
• Oligosaccharides
• Saccharomyces cerevisiae Proteins
• Thy-1 Antigens
• Transferrin
• ALG3 protein, S cerevisiae
• DPM2 protein, human
• Mannosyltransferases
• dolichyl-phosphate beta-D-mannosyltransferase
• Intramolecular Oxidoreductases
• prostaglandin R2 D-isomerase
• Mannose

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• CD59 Antigens (metabolism)
• Carbohydrate Sequence
• Carrier Proteins (genetics)
• Cells, Cultured
• Child, Preschool
• Congenital Disorders of Glycosylation (complications, enzymology, genetics, pathology)
• Endoplasmic Reticulum (metabolism)
• Female
• Fibroblasts (cytology, drug effects, enzymology)
• Fungal Proteins (genetics)
• Glycosylation
• Humans
• Infant
• Intramolecular Oxidoreductases (cerebrospinal fluid)
• Isoenzymes (deficiency, genetics, metabolism)
• Lipocalins
• Male
• Mannose (metabolism, pharmacology)
• Mannosyltransferases (deficiency, genetics, metabolism)
• Membrane Proteins (genetics)
• Mice
• Molecular Sequence Data
• Mutation
• Oligosaccharides (metabolism)
• Saccharomyces cerevisiae Proteins
• Thy-1 Antigens (biosynthesis)
• Transferrin (metabolism)