2. Academic Validation
  3. ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan

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

  • Nat Commun. 2016 May 19;7:11534. doi: 10.1038/ncomms11534.
Isabelle Gerin 1,  Benoît Ury 1,  Isabelle Breloy 2,  Céline Bouchet-Seraphin 3,  Jennifer Bolsée 1,  Mathias Halbout 1,  Julie Graff 1,  Didier Vertommen 1,  Giulio G Muccioli 4,  Nathalie Seta 3,  Jean-Marie Cuisset 5,  Ivana Dabaj 6,  Susana Quijano-Roy 6 7 8,  Ammi Grahn 1,  Emile Van Schaftingen 1,  Guido T Bommer 1
Affiliations

Affiliations

  • 1 WELBIO and de Duve Institute, Biological Chemistry, Université Catholique de Louvain, B-1200 Brussels, Belgium.
  • 2 Institute for Biochemistry II, Medical Faculty, University of Cologne, D-50931 Cologne, Germany.
  • 3 AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Biochimie Métabolique et Cellulaire, F-75018 Paris, France.
  • 4 Louvain Drug Research Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.
  • 5 Hôpital Roger-Salengro, Service de neuropédiatrie, Centre de Référence des Maladies Neuromusculaires, CHRU, F-59000 Lille, France.
  • 6 AP-HP, Hôpital R Poincaré, Service de pédiatrie, F-92380 Garches, France.
  • 7 Centre de Référence des Maladies Neuromusculaires, F-92380 Garches, France.
  • 8 Université de Versailles-St Quentin, U1179 UVSQ - INSERM, F-78180 Montigny, France.
PMID: 27194101 DOI: 10.1038/ncomms11534
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.

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