Title :

A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis

Author(s) :

Wilson, Matthew P. [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Kentache, Takfarinas [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Althoff, Charlotte [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Center for Human Genetics, University of Leuven School of Medicine
Schulz, Celine [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
De Bettignies, Geoffroy [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Mateu Cabrera, Gisèle [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Cimbalistiene, Loreta [Auteur]
Vilnius University [Vilnius]
Burnyte, Birute [Auteur]
Vilnius University [Vilnius]
Yoon, Grace [Auteur]
The Hospital for sick children [Toronto] [SickKids]
University of Toronto
Costain, Gregory [Auteur]
The Hospital for sick children [Toronto] [SickKids]
University of Toronto
Vuillaumier-Barrot, Sandrine [Auteur]
Centre de recherche sur l'Inflammation [CRI (UMR_S_1149 / ERL_8252 / U1149)]
Cheillan, David [Auteur]
Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] [Centre de Biologie et de Pathologie]
Rymen, Daisy [Auteur]
University Hospitals Leuven [Leuven]
Rychtarova, Lucie [Auteur]
1. lékařská fakulta, Univerzita Karlova [Praha, Česká republika] = First Faculty of Medicine, Charles University [Prague, Czech Republic] [1. LF UK / 1st Faculty of Medicine]
Hansikova, Hana [Auteur]
1. lékařská fakulta, Univerzita Karlova [Praha, Česká republika] = First Faculty of Medicine, Charles University [Prague, Czech Republic] [1. LF UK / 1st Faculty of Medicine]
Bury, Marina [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Dewulf, Joseph P. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Caligiore, Francesco [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Jaeken, Jaak [Auteur]
University Hospitals Leuven [Leuven]
Cantagrel, Vincent [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Van Schaftingen, Emile [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Matthijs, Gert [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Bommer, Guido T. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]

Journal title :

Cell

Abbreviated title :

Cell

Publisher :

Elsevier

Publication date :

2024-05-30

ISSN :

0092-8674

English keyword(s) :

dolichol
polyprenol
dolichal
polyprenal
N-glycosylation
pseudoautosomal region
congenital disorders of glycosylation
lipid droplets
polyisoprenoids

HAL domain(s) :

Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

ANR Project :

Exploration des roles de TMEM165 et SPCA1 dans l'homéostasie Golgienne du Ca2+ et du Mn2+, la glycosylation golgienne et la sécrétion des protéines, application aux pathologies TMEM165-CDG et HHD.

Administrative institution(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Submission date :

2024-06-19T11:54:52Z
2024-07-02T14:10:38Z