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.
Cantagrel
Vincent
V
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.
Lefeber
Dirk J
DJ
Ng
Bobby G
BG
Guan
Ziqiang
Z
Silhavy
Jennifer L
JL
Bielas
Stephanie L
SL
Lehle
Ludwig
L
Hombauer
Hans
H
Adamowicz
Maciej
M
Swiezewska
Ewa
E
De Brouwer
Arjan P
AP
Blümel
Peter
P
Sykut-Cegielska
Jolanta
J
Houliston
Scott
S
Swistun
Dominika
D
Ali
Bassam R
BR
Dobyns
William B
WB
Babovic-Vuksanovic
Dusica
D
van Bokhoven
Hans
H
Wevers
Ron A
RA
Raetz
Christian R H
CR
Freeze
Hudson H
HH
Morava
Eva
E
Al-Gazali
Lihadh
L
Gleeson
Joseph G
JG
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
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