FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy.
Animals
Basement Membrane
/ metabolism
Cell Line
Disease Models, Animal
Fibronectins
/ metabolism
Gene Knockout Techniques
Glycosylation
Glycosyltransferases
/ deficiency
Humans
Male
Muscle, Skeletal
/ metabolism
Muscular Dystrophies
/ genetics
Muscular Dystrophies, Limb-Girdle
/ genetics
Muscular Dystrophy, Animal
/ genetics
Mutation
Myoblasts, Skeletal
/ metabolism
Pentosyltransferases
/ deficiency
Phenotype
Zebrafish
Zebrafish Proteins
/ deficiency
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 05 2021
19 05 2021
Historique:
received:
17
03
2020
accepted:
19
04
2021
entrez:
20
5
2021
pubmed:
21
5
2021
medline:
1
6
2021
Statut:
epublish
Résumé
The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.
Identifiants
pubmed: 34012031
doi: 10.1038/s41467-021-23217-6
pii: 10.1038/s41467-021-23217-6
pmc: PMC8134429
doi:
Substances chimiques
Fibronectins
0
Zebrafish Proteins
0
FKRP protein, zebrafish
EC 2.4.-
Glycosyltransferases
EC 2.4.-
FKRP protein, human
EC 2.4.2.-
Pentosyltransferases
EC 2.4.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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