Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate -deficient glycoprotein syndrome, represent a family of genetic diseases wi th variable clinical presentations. Common to all types of CDG characterize d to date is a defective Asn-linked glycosylation caused by enzymatic defec ts of N-glycan synthesis. Previously, we have identified a mutation in the ALG6 alpha 1,3 glucosyltransferase gene as the cause of CDG-Ic in four rela ted patients. Here, we present the identification of seven additional cases of CDG-Ic among a group of 35 untyped CDG patients. Analysis of lipid-link ed oligosaccharides in fibroblasts confirmed the accumulation of dolichyl p yrophosphate-Man(9)GlcNAc(2) in the CDG-Ic patients. The genomic organizati on of the human ALG6 gene was determined, revealing 14 exons spread over 55 kb. By polymerase chain reaction amplification and sequencing of ALG6 exon s, three mutations, in addition to the previously described A333 V substitu tion, were detected in CDG-Ic patients. The detrimental effect of these mut ations on ALG6 activity was confirmed by complementation of alg6 yeast muta nts, Haplotype analysis of CDG-Ic patients revealed a founder effect for th e ALG6 allele bearing the A333 V mutation. Although more than 80% of CDG ar e type Ia, CDO-Ic may be the second most common form of the disease.