Journal
CELL
Volume 142, Issue 2, Pages 203-217Publisher
CELL PRESS
DOI: 10.1016/j.cell.2010.06.001
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Funding
- Rocket Fund [R01 DK55615]
- Sanford Children's Health Research Center
- Euroglycanet [LSHM-CT2005-512131]
- Metakids and the Netherlands Brain Foundation
- Deutsche Forschungsgemeinschaft
- Korber-Stiftung
- National Institutes of Health [GM-069338]
- Fondation pour la Recherche Medicale
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N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5 alpha-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.
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