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A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis.

Abstract
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.
AuthorsChristian Thiel, Markus Schwarz, Jianhe Peng, Michal Grzmil, Martin Hasilik, Thomas Braulke, Alfried Kohlschütter, Kurt von Figura, Ludwig Lehle, Christian Körner
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 25 Pg. 22498-505 (Jun 20 2003) ISSN: 0021-9258 [Print] United States
PMID12684507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA Primers
  • Dolichol Phosphates
  • Dolichols
  • Oligosaccharides
  • Polyisoprenyl Phosphate Monosaccharides
  • dolichol pyrophosphate
  • N-acetylglucosaminylpyrophosphoryldolichol
Topics
  • Base Sequence
  • Carbohydrate Metabolism, Inborn Errors (genetics)
  • Carbohydrate Sequence
  • Cell Line
  • DNA Primers
  • Dolichol Phosphates (metabolism)
  • Dolichols (metabolism)
  • Female
  • Fibroblasts
  • Genetic Complementation Test
  • Glycosylation
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oligosaccharides (biosynthesis)
  • Pedigree
  • Polyisoprenyl Phosphate Monosaccharides (metabolism)
  • Saccharomyces cerevisiae (genetics, metabolism)
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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