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 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.