FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
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FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy. / Wood, A J; Lin, C H; Li, M; Nishtala, K; Alaei, S; Rossello, F; Sonntag, C; Hersey, L; Miles, L B; Krisp, C; Dudczig, S; Fulcher, A J; Gibertini, S; Conroy, P J; Siegel, A; Mora, M; Jusuf, P; Packer, N H; Currie, P D.
In: NAT COMMUN, Vol. 12, No. 1, 2951, 19.05.2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
AU - Wood, A J
AU - Lin, C H
AU - Li, M
AU - Nishtala, K
AU - Alaei, S
AU - Rossello, F
AU - Sonntag, C
AU - Hersey, L
AU - Miles, L B
AU - Krisp, C
AU - Dudczig, S
AU - Fulcher, A J
AU - Gibertini, S
AU - Conroy, P J
AU - Siegel, A
AU - Mora, M
AU - Jusuf, P
AU - Packer, N H
AU - Currie, P D
PY - 2021/5/19
Y1 - 2021/5/19
N2 - 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.
AB - 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.
KW - Animals
KW - Basement Membrane/metabolism
KW - Cell Line
KW - Disease Models, Animal
KW - Fibronectins/metabolism
KW - Gene Knockout Techniques
KW - Glycosylation
KW - Glycosyltransferases/deficiency
KW - Humans
KW - Male
KW - Muscle, Skeletal/metabolism
KW - Muscular Dystrophies/genetics
KW - Muscular Dystrophies, Limb-Girdle/genetics
KW - Muscular Dystrophy, Animal/genetics
KW - Mutation
KW - Myoblasts, Skeletal/metabolism
KW - Pentosyltransferases/deficiency
KW - Phenotype
KW - Zebrafish
KW - Zebrafish Proteins/deficiency
U2 - 10.1038/s41467-021-23217-6
DO - 10.1038/s41467-021-23217-6
M3 - SCORING: Journal article
C2 - 34012031
VL - 12
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
M1 - 2951
ER -