Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.
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.
Imbach
T
T
Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
Schenk
B
B
Schollen
E
E
Burda
P
P
Stutz
A
A
Grunewald
S
S
Bailie
N M
NM
King
M D
MD
Jaeken
J
J
Matthijs
G
G
Berger
E G
EG
Aebi
M
M
Hennet
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018957:CD59 Antigens / Q000378:metabolism; D002240:Carbohydrate Sequence; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005656:Fungal Proteins / Q000235:genetics; D006031:Glycosylation; D006801:Humans; D007223:Infant; D019746:Intramolecular Oxidoreductases / Q000134:cerebrospinal fluid; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins; D008297:Male; D008358:Mannose / Q000378:metabolism / Q000494:pharmacology; D008364:Mannosyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009844:Oligosaccharides / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D018800:Thy-1 Antigens / Q000096:biosynthesis; D014168:Transferrin / Q000378:metabolism
D018957:CD59 Antigens; D002352:Carrier Proteins; D005656:Fungal Proteins; D007527:Isoenzymes; D054834:Lipocalins; D008565:Membrane Proteins; D009844:Oligosaccharides; D029701:Saccharomyces cerevisiae Proteins; D018800:Thy-1 Antigens; D014168:Transferrin; C104466:ALG3 protein, S cerevisiae; C115077:DPM2 protein, human; D008364:Mannosyltransferases; C022755:dolichyl-phosphate beta-D-mannosyltransferase; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D008358:Mannose