期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11534
关键词
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资金
- WELBIO
- Fondation Marie-Marguerite Delacroix
- Fondation contre le Cancer
- FNRS
- FSR
- FRIA
- IAP VII (Interuniversity Attraction Pole) [P7/43]
- MASSMET
- DFG [BR 3979/1-1]
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.
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