A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis
| Autor: | Thomas Braulke, Markus Schwarz, Christian Körner, Jianhe Peng, Kurt von Figura, Alfried Kohlschütter, Michal Grzmil, Ludwig Lehle, Christian Thiel, Martin Hasilik |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Mannosyltransferase Glycosylation Saccharomyces cerevisiae Mutant Molecular Sequence Data Oligosaccharides Biology Biochemistry Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Dolichol Complementary DNA Dolichols Humans Molecular Biology 030304 developmental biology DNA Primers Dolichol Phosphates 0303 health sciences Polyisoprenyl Phosphate Monosaccharides Base Sequence Genetic Complementation Test Wild type Cell Biology Fibroblasts biology.organism_classification 3. Good health Pedigree chemistry Carbohydrate Sequence Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Mannosyltransferase activity Mutagenesis Site-Directed lipids (amino acids peptides and proteins) Female 030217 neurology & neurosurgery Carbohydrate Metabolism Inborn Errors |
| Zdroj: | The Journal of biological chemistry. 278(25) |
| ISSN: | 0021-9258 |
| Popis: | Deficiency of GDP-Man:Man1GlcNAc2-PP-dolichol mannosyltransferase (hALG2), is the cause of a new type of congenital disorders of glycosylation (CDG) designated CDG-Ii. The patient presented normal at birth but developed in the 1st year of life a multisystemic disorder with mental retardation, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities. An accumulation of Man1GlcNAc2-PP-dolichol and Man2GlcNAc2-PP-dolichol was observed in skin fibroblasts of the patient. Incubation of patient fibroblast extracts with Man1GlcNAc2-PP-dolichol and GDP-mannose revealed a severely reduced activity of the mannosyltransferase elongating Man1GlcNAc2-PP dolichol. Because the Saccharomyces cerevisiae mutant alg2-1 was known to accumulate the same shortened dolichol-linked oligosaccharides as the patient, the yeast ALG2 sequence was used to identify the human ortholog. Genetic analysis revealed that the patient was heterozygous for a single nucleotide deletion and a single nucleotide substitution in the human ortholog of yeast ALG2. Expression of wild type but not of mutant hALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in the alg2-1 yeast cells. hALG2 was shown to act as an alpha1,3-mannosyltransferase. The resulting Manalpha1,3-ManGlcNAc2-PP dolichol is further elongated by a yet unknown alpha1,6-mannosyltransferase. |
| Databáze: | OpenAIRE |
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