title: Deficiency of dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl mannosyltransferase causes congenital disorder of glycosylation type Ig.
abstract: Deficiency of the endoplasmic reticulum enzyme dolichyl-phosphate mannose (Dol-P-Man):Man(7)GlcNAc(2)-PP-dolichyl mannosyltransferase leads to a new type of congenital disorder of glycosylation, designated type Ig. The patient 1 presented with a multisystemic disorder with microcephaly, developmental retardation, convulsions and dysmorphic signs. The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete N-glycan side chains. In skin fibroblasts from the patient, the activity of Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol mannosyltransferase was severely reduced leading to the accumulation of Man(7)GlcNAc(2)-PP-Dol, which was transferred to newly synthesized glycoproteins. Sequencing of the Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol mannosyltransferase cDNA revealed a compound heterozygosity for two point mutations, leading to the exchange of leucine(158) for a proline residue and a premature translation stop with loss of the C-terminal 74 amino acids. The parents were heterozygous for one of the two mutations. Retroviral expression of the wild-type Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol mannosyltransferase cDNA in patient's fibroblasts normalized the mannosyltransferase activity.
authors.affiliation: Georg-August-Universität zu Göttingen, Abteilung Biochemie II, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.forename: Markus
authors.initials: M
authors.lastname: Schwarz
authors.forename: Martin
authors.initials: M
authors.lastname: Hasilik
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grieben
authors.forename: Folker
authors.initials: F
authors.lastname: Hanefeld
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lehle
authors.forename: Kurt
authors.initials: K
authors.lastname: von Figura
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005816:Genetic Complementation Test; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D007525:Isoelectric Focusing; D008364:Mannosyltransferases / Q000172:deficiency* / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009844:Oligosaccharides / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation; D012190:Retroviridae / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D009844:Oligosaccharides; D014168:Transferrin; D008364:Mannosyltransferases; C474311:dolichyl-phosphate mannose Man(7)GlcNAc(2)-PP-dolichyl mannosyltransferase