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SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.

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 5alpha-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.

Pubmed ID: 20637498


  • Cantagrel V
  • Lefeber DJ
  • Ng BG
  • Guan Z
  • Silhavy JL
  • Bielas SL
  • Lehle L
  • Hombauer H
  • Adamowicz M
  • Swiezewska E
  • De Brouwer AP
  • Bl├╝mel P
  • Sykut-Cegielska J
  • Houliston S
  • Swistun D
  • Ali BR
  • Dobyns WB
  • Babovic-Vuksanovic D
  • van Bokhoven H
  • Wevers RA
  • Raetz CR
  • Freeze HH
  • Morava E
  • Al-Gazali L
  • Gleeson JG



Publication Data

July 23, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK80506
  • Agency: NINDS NIH HHS, Id: P30 NS047101
  • Agency: NINDS NIH HHS, Id: P30 NS047101
  • Agency: NINDS NIH HHS, Id: P30 NS047101-09
  • Agency: NIDDK NIH HHS, Id: R01 DK055615
  • Agency: NIDDK NIH HHS, Id: R01 DK55615
  • Agency: NINDS NIH HHS, Id: R01 NS048453
  • Agency: NINDS NIH HHS, Id: R01 NS048453-08
  • Agency: NINDS NIH HHS, Id: R01 NS052455
  • Agency: NINDS NIH HHS, Id: R01 NS052455-05
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Abnormalities, Multiple
  • Animals
  • Butadienes
  • Consanguinity
  • Dolichol
  • Embryo, Mammalian
  • Genome-Wide Association Study
  • Glycosylation
  • Hemiterpenes
  • Humans
  • Intellectual Disability
  • Membrane Proteins
  • Mice
  • Mutation
  • Pentanes
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Unfolded Protein Response