title: ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan.
abstract: Mutations in genes required for the glycosylation of α-dystroglycan lead to muscle and brain diseases known as dystroglycanopathies. However, the precise structure and biogenesis of the assembled glycan are not completely understood. Here we report that three enzymes mutated in dystroglycanopathies can collaborate to attach ribitol phosphate onto α-dystroglycan. Specifically, we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan. We also show that ISPD and FKTN are essential for the incorporation of ribitol into α-dystroglycan in HEK293 cells. Glycosylation of α-dystroglycan in fibroblasts from patients with hypomorphic ISPD mutations is reduced. We observe that in some cases glycosylation can be partially restored by addition of ribitol to the culture medium, suggesting that dietary supplementation with ribitol should be evaluated as a therapy for patients with ISPD mutations.
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gerin
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Benoît
authors.initials: B
authors.lastname: Ury
authors.affiliation: Institute for Biochemistry II, Medical Faculty, University of Cologne, D-50931 Cologne, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Breloy
authors.affiliation: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Biochimie Métabolique et Cellulaire, F-75018 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bouchet-Seraphin
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bolsée
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Mathias
authors.identifier: http://orcid.org/0000-0002-3011-0476
authors.initials: M
authors.lastname: Halbout
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Graff
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Vertommen
authors.affiliation: Louvain Drug Research Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Giulio G
authors.identifier: http://orcid.org/0000-0002-1600-9259
authors.initials: GG
authors.lastname: Muccioli
authors.affiliation: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Biochimie Métabolique et Cellulaire, F-75018 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Seta
authors.affiliation: Hôpital Roger-Salengro, Service de neuropédiatrie, Centre de Référence des Maladies Neuromusculaires, CHRU, F-59000 Lille, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuisset
authors.affiliation: AP-HP, Hôpital R Poincaré, Service de pédiatrie, F-92380 Garches, France.
authors.forename: Ivana
authors.initials: I
authors.lastname: Dabaj
authors.affiliation: AP-HP, Hôpital R Poincaré, Service de pédiatrie, F-92380 Garches, France.|Centre de Référence des Maladies Neuromusculaires, F-92380 Garches, France.|Université de Versailles-St Quentin, U1179 UVSQ - INSERM, F-78180 Montigny, France.
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Ammi
authors.initials: A
authors.lastname: Grahn
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
authors.affiliation: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Guido T
authors.initials: GT
authors.lastname: Bommer
mesh_terms: D000818:Animals; D049030:Dystroglycans / Q000378:metabolism*; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D010430:Pentosyltransferases; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D012266:Ribose / Q000378:metabolism
chemical_list: C113587:FKTN protein, human; D008565:Membrane Proteins; D009702:Nucleoside Diphosphate Sugars; D011506:Proteins; D049030:Dystroglycans; C100069:cytidine diphosphate ribitol; D012266:Ribose; C443107:FKRP protein, human; D010430:Pentosyltransferases; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human