T. Imbach et al., Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie, J CLIN INV, 105(2), 2000, pp. 233-239
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 dysmorphi
c features. We detected hypoglycosylation on serum transferrin and cerebros
pinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endopl
asmic reticulum of patient fibroblasts showed an accumulation of the dolich
yl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dol
ichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in t
hese 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 imp
rove the glycosylation status of DPM1-deficient fibroblast cells, thus prec
luding a possible therapeutic application of mannose in the patients. Becau
se DPM1 deficiency, Like other subtypes of CDG-I, impairs the assembly of N
-glycans, this novel glycosylation defect was named CDG-Ie.