A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis

Matthew P Wilson; Takfarinas Kentache; Charlotte R Althoff; Céline Schulz; Geoffroy de Bettignies; Gisèle Mateu Cabrera; Loreta Cimbalistiene; Birute Burnyte; Grace Yoon; Gregory Costain; Sandrine Vuillaumier-Barrot; David Cheillan; Daisy Rymen; Lucie Rychtarova; Hana Hansikova; Marina Bury; Joseph P Dewulf; Francesco Caligiore; Jaak Jaeken; Vincent Cantagrel; Emile Van Schaftingen; Gert Matthijs; François Foulquier; Guido T Bommer

doi:10.1016/j.cell.2024.04.041

A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis

Cell. 2024 Jul 11;187(14):3585-3601.e22. doi: 10.1016/j.cell.2024.04.041. Epub 2024 May 30.

Authors

Matthew P Wilson¹, Takfarinas Kentache², Charlotte R Althoff³, Céline Schulz⁴, Geoffroy de Bettignies⁴, Gisèle Mateu Cabrera¹, Loreta Cimbalistiene⁵, Birute Burnyte⁵, Grace Yoon⁶, Gregory Costain⁷, Sandrine Vuillaumier-Barrot⁸, David Cheillan⁹, Daisy Rymen¹⁰, Lucie Rychtarova¹¹, Hana Hansikova¹¹, Marina Bury², Joseph P Dewulf², Francesco Caligiore², Jaak Jaeken¹⁰, Vincent Cantagrel¹², Emile Van Schaftingen¹³, Gert Matthijs¹⁴, François Foulquier¹⁵, Guido T Bommer¹⁶

Affiliations

¹ Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, Leuven, Belgium.
² Metabolic Research Group, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium.
³ Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, Leuven, Belgium; Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
⁴ Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
⁵ Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
⁶ Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada; Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
⁷ Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁸ AP-HP, Biochimie Métabolique et Cellulaire and Département de Génétique, Hôpital Bichat-Claude Bernard, and Université de Paris, Faculté de Médecine Xavier Bichat, INSERM U1149, CRI, Paris, France.
⁹ Service Biochimie et Biologie Moléculaire - Hospices Civils de Lyon; Laboratoire Carmen - Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Lyon, France.
¹⁰ Department of Pediatrics, Center for Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium.
¹¹ Laboratory for Study of Mitochondrial Disorders, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czechia.
¹² Developmental Brain Disorders Laboratory, Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France.
¹³ Metabolic Research Group, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium. Electronic address: [email protected].
¹⁴ Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
¹⁵ Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France. Electronic address: [email protected].
¹⁶ Metabolic Research Group, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium. Electronic address: [email protected].

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.

Keywords: N-glycosylation; congenital disorders of glycosylation; dolichal; dolichol; lipid droplets; polyisoprenoids; polyprenal; polyprenol; pseudoautosomal region.

MeSH terms

3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
Congenital Disorders of Glycosylation / genetics
Congenital Disorders of Glycosylation / metabolism
Dolichols* / biosynthesis
Dolichols* / metabolism
Female
Glycosylation
Humans
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mutation, Missense

Substances

Dolichols
SRD5A3 protein, human
3-Oxo-5-alpha-Steroid 4-Dehydrogenase
Membrane Proteins