%0 Journal Article
%T A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis.
%A Wilson MP
%A Kentache T
%A Althoff CR
%A Schulz C
%A de Bettignies G
%A Mateu Cabrera G
%A Cimbalistiene L
%A Burnyte B
%A Yoon G
%A Costain G
%A Vuillaumier-Barrot S
%A Cheillan D
%A Rymen D
%A Rychtarova L
%A Hansikova H
%A Bury M
%A Dewulf JP
%A Caligiore F
%A Jaeken J
%A Cantagrel V
%A Van Schaftingen E
%A Matthijs G
%A Foulquier F
%A Bommer GT
%J Cell
%V 187
%N 14
%D 2024 Jul 11
%M 38821050
%F 66.85
%R 10.1016/j.cell.2024.04.041
%X Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.