ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan

Isabelle Gerin, Benoît Ury, Isabelle Breloy, Céline Bouchet-Seraphin, Jennifer Bolsée, Mathias Halbout, Julie Graff, Didier Vertommen, Giulio G. Muccioli, Nathalie Seta, Jean-Marie Cuisset, Ivana Dabaj, Susana Quijano-Roy, Ammi Grahn, Emile Van Schaftingen and Guido T. Bommer ()
Additional contact information
Isabelle Gerin: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Benoît Ury: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Isabelle Breloy: Institute for Biochemistry II, Medical Faculty, University of Cologne
Céline Bouchet-Seraphin: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Biochimie Métabolique et Cellulaire
Jennifer Bolsée: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Mathias Halbout: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Julie Graff: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Didier Vertommen: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Giulio G. Muccioli: Louvain Drug Research Institute, Université Catholique de Louvain
Nathalie Seta: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Biochimie Métabolique et Cellulaire
Jean-Marie Cuisset: Hôpital Roger-Salengro, Service de neuropédiatrie, Centre de Référence des Maladies Neuromusculaires, CHRU
Ivana Dabaj: AP-HP, Hôpital R Poincaré, Service de pédiatrie
Susana Quijano-Roy: AP-HP, Hôpital R Poincaré, Service de pédiatrie
Ammi Grahn: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Emile Van Schaftingen: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain
Guido T. Bommer: WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11534

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