title: ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg.
abstract: In the endoplasmic reticulum (ER) of eukaryotes, N-linked glycans are first assembled on the lipid carrier dolichyl pyrophosphate. The GlcNAc(2)Man(9)Glc(3) oligosaccharide is transferred to selected asparagine residues of nascent polypeptides. Defects along the biosynthetic pathway of N-glycans are associated with severe multisystemic syndromes called congenital disorders of glycosylation. Here, we describe a deficiency in the ALG12 ER alpha1,6-mannosyltransferase resulting in a novel type of glycosylation disorder. The severe disease was identified in a child presenting with psychomotor retardation, hypotonia, growth retardation, dysmorphic features and anorexia. In the patient's fibroblasts, the biosynthetic intermediate GlcNAc(2)Man(7) oligosaccharide was detected both on the lipid carrier dolichyl pyrophosphate and on newly synthesized glycoproteins, thus pointing to a defect in the dolichyl pyrophosphate-GlcNAc(2)Man(7)-dependent ALG12 alpha1,6 mannosyltransferase. Analysis of the ALG12 cDNA in the CDG patient revealed compound heterozygosity for two point mutations that resulted in the amino acid substitutions T67M and R146Q, respectively. The impact of these mutations on ALG12 protein function was investigated in the Saccharomyces cerevisiae alg12 glycosylation mutant by showing that the yeast ALG12 gene bearing the homologous mutations T61M and R161Q and the human mutant ALG12 cDNA alleles failed to normalize the growth defect phenotype of the alg12 yeast model, whereas expression of the normal ALG12 cDNA complemented the yeast mutation. The ALG12 mannosyltransferase defect defines a new type of congenital disorder of glycosylation, designated CDG-Ig.
authors.affiliation: Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Grubenmann
authors.forename: Christian G
authors.initials: CG
authors.lastname: Frank
authors.forename: Susanne
authors.initials: S
authors.lastname: Kjaergaard
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; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008297:Male; D008364:Mannosyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008969:Molecular Sequence Data; D009122:Muscle Hypertonia / Q000235:genetics; D010641:Phenotype; D011596:Psychomotor Disorders / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D008364:Mannosyltransferases