A mutation in the human ortholog of theSaccharomyces cerevisiae ALG6gene causes carbohydrate-deficient glycoprotein syndrome type-Ic

Publisher Website
Google Scholar
Abstract
Carbohydrate-deficient glycoprotein syndrome (CDGS) represents a class of genetic diseases characterized by abnormal N-linked glycosylation. CDGS patients show a large number of glycoprotein abnormalities resulting in dysmorphy, encephalopathy, and other organ disorders. The majority of CDGSs described to date are related to an impaired biosynthesis of dolichyl pyrophosphate-linked Glc3Man9GlcNAc2in the endoplasmic reticulum. Recently, we identified in four related patients a novel type of CDGS characterized by an accumulation of dolichyl pyrophosphate-linked Man9GlcNAc2. Elaborating on the analogy of this finding with the phenotype ofalg5andalg6 Saccharomyces cerevisiaestrains, we have cloned and analyzed the human orthologs to theALG5dolichyl phosphate glucosyltransferase andALG6dolichyl pyrophosphate Man9GlcNAc2α1,3-glucosyltransferase in four novel CDGS patients. AlthoughALG5was not altered in the patients, a C→T transition was detected inALG6cDNA of all four CDGS patients. The mutation cosegregated with the disease in a Mendelian recessive manner. Expression of the humanALG5andALG6cDNA could partially complement the respectiveS. cerevisiae alg5andalg6deficiency. By contrast, the mutantALG6cDNA of CDGS patients failed to revert the hypoglycosylation observed inalg6yeasts, thereby proving a functional relationship between the alanine to valine substitution introduced by the C→T transition and the CDGS phenotype. The mutation in theALG6α1,3-glucosyltransferase gene defines an additional type of CDGS, which we propose to refer to as CDGS type-Ic.