{Reference Type}: Journal Article
{Title}: A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis.
{Author}: Wilson MP;Kentache T;Althoff CR;Schulz C;de Bettignies G;Mateu Cabrera G;Cimbalistiene L;Burnyte B;Yoon G;Costain G;Vuillaumier-Barrot S;Cheillan D;Rymen D;Rychtarova L;Hansikova H;Bury M;Dewulf JP;Caligiore F;Jaeken J;Cantagrel V;Van Schaftingen E;Matthijs G;Foulquier F;Bommer GT;
{Journal}: Cell
{Volume}: 187
{Issue}: 14
{Year}: 2024 Jul 11
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2024.04.041
{Abstract}: 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.