title: Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL.
abstract: Defects of lipid-linked oligosaccharide assembly lead to alterations of N-linked glycosylation known as "type I congenital disorders of glycosylation" (CDG). Dysfunctions along this stepwise assembly pathway are characterized by intracellular accumulation of intermediate lipid-linked oligosaccharides, the detection of which contributes to the identification of underlying enzymatic defects. Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures, which was paralleled by the transfer of incomplete oligosaccharides precursors to protein. A homozygous point-mutation 1567G-->A (amino acid substitution E523K) was detected in the ALG9 gene. The functional homology between the human ALG9 and Saccharomyces cerevisiae ALG9, as well as the deleterious effect of the E523K mutation detected in the patient with CDG, were confirmed by a yeast complementation assay lacking the ALG9 gene. The ALG9 defect found in the patient with CDG--who presented with developmental delay, hypotonia, seizures, and hepatomegaly--shows that efficient lipid-linked oligosaccharide synthesis is required for proper human development and physiology. The ALG9 defect presented here defines a novel form of CDG named "CDG-IL."
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Frank
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Grubenmann
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Eric G
authors.initials: EG
authors.lastname: Berger
authors.forename: Markus
authors.initials: M
authors.lastname: Aebi
authors.forename: Thierry
authors.initials: T
authors.lastname: Hennet
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005816:Genetic Complementation Test; D006031:Glycosylation; D006529:Hepatomegaly / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000378:metabolism; D008364:Mannosyltransferases / Q000172:deficiency / Q000235:genetics*; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D012640:Seizures / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D008070:Lipopolysaccharides; D029701:Saccharomyces cerevisiae Proteins; C023023:lipid-linked oligosaccharides; C068701:KRE2 protein, S cerevisiae; D008364:Mannosyltransferases