Gerin, Isabelle, Ury, Benoit, Breloy, Isabelle, Bouchet-Seraphin, Celine, Bolsee, Jennifer, Halbout, Mathias ORCID: 0000-0002-3011-0476, Graff, Julie, Vertommen, Didier ORCID: 0000-0001-7648-8282, Muccioli, Giulio G., Seta, Nathalie, Cuisset, Jean-Marie, Dabaj, Ivana ORCID: 0000-0002-2324-1208, Quijano-Roy, Susana, Grahn, Ammi, Van Schaftingen, Emile ORCID: 0000-0002-6199-7647 and Bommer, Guido T. (2016). ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto alpha-dystroglycan. Nat. Commun., 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

Mutations in genes required for the glycosylation of alpha-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 a-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 alpha-dystroglycan. We also show that ISPD and FKTN are essential for the incorporation of ribitol into alpha-dystroglycan in HEK293 cells. Glycosylation of alpha-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gerin, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ury, BenoitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Breloy, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouchet-Seraphin, CelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolsee, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halbout, MathiasUNSPECIFIEDorcid.org/0000-0002-3011-0476UNSPECIFIED
Graff, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vertommen, DidierUNSPECIFIEDorcid.org/0000-0001-7648-8282UNSPECIFIED
Muccioli, Giulio G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seta, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cuisset, Jean-MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dabaj, IvanaUNSPECIFIEDorcid.org/0000-0002-2324-1208UNSPECIFIED
Quijano-Roy, SusanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grahn, AmmiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Schaftingen, EmileUNSPECIFIEDorcid.org/0000-0002-6199-7647UNSPECIFIED
Bommer, Guido T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-276856
DOI: 10.1038/ncomms11534
Journal or Publication Title: Nat. Commun.
Volume: 7
Date: 2016
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CONGENITAL MUSCULAR-DYSTROPHY; WALKER-WARBURG SYNDROME; GRAM-POSITIVE BACTERIA; FUKUTIN-RELATED PROTEIN; O-MANNOSYLATION; HAEMOPHILUS-INFLUENZAE; MAMMALIAN-CELLS; POSTTRANSLATIONAL MODIFICATION; STREPTOCOCCUS-PNEUMONIAE; EXTRACELLULAR-MATRIXMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27685

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