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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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CD59 Antigens / metabolism
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Carbohydrate Sequence
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Carrier Proteins / genetics
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Cells, Cultured
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Child, Preschool
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Congenital Disorders of Glycosylation / complications
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Congenital Disorders of Glycosylation / enzymology*
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Congenital Disorders of Glycosylation / genetics*
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Congenital Disorders of Glycosylation / pathology
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Endoplasmic Reticulum / metabolism
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Female
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Fungal Proteins / genetics
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Glycosylation
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Humans
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Infant
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Intramolecular Oxidoreductases / cerebrospinal fluid
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Lipocalins
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Male
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Mannose / metabolism
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Mannose / pharmacology
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Mannosyltransferases / deficiency*
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Mannosyltransferases / genetics*
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Mannosyltransferases / metabolism
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Membrane Proteins / genetics
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Mice
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Molecular Sequence Data
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Mutation
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Oligosaccharides / metabolism
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Saccharomyces cerevisiae Proteins*
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Thy-1 Antigens / biosynthesis
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Transferrin / metabolism
Substances
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CD59 Antigens
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Carrier Proteins
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Fungal Proteins
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Isoenzymes
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Lipocalins
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Membrane Proteins
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Oligosaccharides
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Saccharomyces cerevisiae Proteins
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Thy-1 Antigens
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Transferrin
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ALG3 protein, S cerevisiae
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DPM2 protein, human
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Mannosyltransferases
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dolichyl-phosphate beta-D-mannosyltransferase
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Intramolecular Oxidoreductases
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prostaglandin R2 D-isomerase
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Mannose