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.