title: SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.
abstract: 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.
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Bielas
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lehle
authors.forename: Hans
authors.initials: H
authors.lastname: Hombauer
authors.forename: Maciej
authors.initials: M
authors.lastname: Adamowicz
authors.forename: Ewa
authors.initials: E
authors.lastname: Swiezewska
authors.forename: Arjan P
authors.initials: AP
authors.lastname: De Brouwer
authors.forename: Peter
authors.initials: P
authors.lastname: Blümel
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sykut-Cegielska
authors.forename: Scott
authors.initials: S
authors.lastname: Houliston
authors.forename: Dominika
authors.initials: D
authors.lastname: Swistun
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Dusica
authors.initials: D
authors.lastname: Babovic-Vuksanovic
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000015:Abnormalities, Multiple / Q000378:metabolism*; D000818:Animals; D002070:Butadienes / Q000378:metabolism; D003241:Consanguinity; D004286:Dolichols / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D055106:Genome-Wide Association Study; D006031:Glycosylation; D045782:Hemiterpenes / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010420:Pentanes / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D002070:Butadienes; C551436:DFG10 protein, S cerevisiae; D004286:Dolichols; D045782:Hemiterpenes; D008565:Membrane Proteins; D010420:Pentanes; D029701:Saccharomyces cerevisiae Proteins; C005059:isoprene; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548469:SRD5A3 protein, human; C548471:Srd5a3 protein, mouse