title: A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.
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 Glc3Man9GlcNAc2 in 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 of alg5 and alg6 Saccharomyces cerevisiae strains, we have cloned and analyzed the human orthologs to the ALG5 dolichyl phosphate glucosyltransferase and ALG6 dolichyl pyrophosphate Man9GlcNAc2 alpha1,3-glucosyltransferase in four novel CDGS patients. Although ALG5 was not altered in the patients, a C-->T transition was detected in ALG6 cDNA of all four CDGS patients. The mutation cosegregated with the disease in a Mendelian recessive manner. Expression of the human ALG5 and ALG6 cDNA could partially complement the respective S. cerevisiae alg5 and alg6 deficiency. By contrast, the mutant ALG6 cDNA of CDGS patients failed to revert the hypoglycosylation observed in alg6 yeasts, thereby proving a functional relationship between the alanine to valine substitution introduced by the C-->T transition and the CDGS phenotype. The mutation in the ALG6 alpha1,3-glucosyltransferase gene defines an additional type of CDGS, which we propose to refer to as CDGS type-Ic.
authors.affiliation: Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Imbach
authors.forename: P
authors.initials: P
authors.lastname: Burda
authors.forename: P
authors.initials: P
authors.lastname: Kuhnert
authors.forename: R A
authors.initials: RA
authors.lastname: Wevers
authors.forename: M
authors.initials: M
authors.lastname: Aebi
authors.forename: E G
authors.initials: EG
authors.lastname: Berger
authors.forename: T
authors.initials: T
authors.lastname: Hennet
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018981:Congenital Disorders of Glycosylation / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005964:Glucosyltransferases / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment; D017421:Sequence Analysis
chemical_list: D018076:DNA, Complementary; D008565:Membrane Proteins; C498467:ALG6 protein, human; D005964:Glucosyltransferases; C119841:dolichyl pyrophosphate Man(9)GlcNAc(2) alpha1,3-glucosyltransferase; C498465:ALG5 protein, human