FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

A. J. Wood; C. H. Lin; M. Li; K. Nishtala; S. Alaei; F. Rossello; C. Sonntag; L. Hersey; L. B. Miles; C. Krisp; S. Dudczig; A. J. Fulcher; S. Gibertini; P. J. Conroy; A. Siegel; Marina Mora; P. Jusuf; N. H. Packer; P. D. Currie

doi:10.1038/s41467-021-23217-6

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

A. J. Wood, C. H. Lin, M. Li, K. Nishtala, S. Alaei, F. Rossello, C. Sonntag, L. Hersey, L. B. Miles, C. Krisp, S. Dudczig, A. J. Fulcher, S. Gibertini, P. J. Conroy, A. Siegel, Marina Mora, P. Jusuf, N. H. Packer, P. D. Currie^*

^*Corresponding author for this work

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Abstract

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.

Original language	English
Article number	2951
Pages (from-to)	1-12
Number of pages	12
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23217-6
Publication status	Published - 19 May 2021

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Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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10.1038/s41467-021-23217-6

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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. (2021). FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy. Nature Communications, 12(1), 1-12. Article 2951. https://doi.org/10.1038/s41467-021-23217-6

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title = "FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy",

abstract = "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{\textquoteright}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.",

author = "Wood, {A. J.} and Lin, {C. H.} and M. Li and K. Nishtala and S. Alaei and F. Rossello and C. Sonntag and L. Hersey and Miles, {L. B.} and C. Krisp and S. Dudczig and Fulcher, {A. J.} and S. Gibertini and Conroy, {P. J.} and A. Siegel and Marina Mora and P. Jusuf and Packer, {N. H.} and Currie, {P. D.}",

note = "Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

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Wood, AJ, Lin, CH, Li, M, Nishtala, K, Alaei, S, Rossello, F, Sonntag, C, Hersey, L, Miles, LB, Krisp, C, Dudczig, S, Fulcher, AJ, Gibertini, S, Conroy, PJ, Siegel, A, Mora, M, Jusuf, P, Packer, NH & Currie, PD 2021, 'FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy', Nature Communications, vol. 12, no. 1, 2951, pp. 1-12. https://doi.org/10.1038/s41467-021-23217-6

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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, Marina

AU - Jusuf, P.

AU - Packer, N. H.

AU - Currie, P. D.

N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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.

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JF - Nature Communications

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ER -

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

Abstract

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Defining the role of glycosylation in basement membrane failure during muscular dystrophy

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FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

Abstract

Bibliographical note

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Defining the role of glycosylation in basement membrane failure during muscular dystrophy

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