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: Christian Thiel, Markus Schwarz, Martin Hasilik, Ulrike Grieben, Folker Hanefeld, Ludwig Lehle, Kurt von Figura, Christian Körner
• Journal: The Biochemical journal (Biochem J) Vol. 367 Issue Pt 1 Pg. 195-201 (Oct 01 2002) ISSN: 0264-6021 [Print] England
• PMID: 12093361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Complementary
• Oligosaccharides
• Transferrin
• Mannosyltransferases
• dolichyl-phosphate mannose Man(7)GlcNAc(2)-PP-dolichyl mannosyltransferase

Topics

• Chromatography, High Pressure Liquid
• DNA Mutational Analysis
• DNA, Complementary (metabolism)
• Electrophoresis, Polyacrylamide Gel
• Endoplasmic Reticulum (metabolism)
• Female
• Fibroblasts (enzymology)
• Genetic Complementation Test
• Genetic Diseases, Inborn (genetics)
• Glycosylation
• Humans
• Isoelectric Focusing
• Mannosyltransferases (deficiency, physiology)
• Mutagenesis, Site-Directed
• Oligosaccharides (metabolism)
• Phenotype
• Point Mutation
• Retroviridae (metabolism)
• Transferrin (metabolism)