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; M. 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
, M. Mora
, P. Jusuf
, N. H. Packer
, P. D. Currie

Research output: Contribution to journal › Article › Research › peer-review

25 Citations (Scopus)

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
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 - Dec 2021

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10.1038/s41467-021-23217-6Licence: CC BY

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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), Article 2951. https://doi.org/10.1038/s41467-021-23217-6

@article{1ff80f7d597f4288ac42b16aa126b8a6,

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 M. Mora and P. Jusuf and Packer, \{N. H.\} and Currie, \{P. D.\}",

note = "Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (PDC, NP: APP1127741, PDC: APP1136567, APP3151883). Australian Research Council Linkage (PDC: LP120100281) in collaboration with Sigma-Aldrich and LIEF Grant (LE150100110). The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. We acknowledge J Callaghan, I Harper, Monash Micro Imaging Facility, J Clark and A Costin, Monash Electron Microscopy Facility, L Kautto, Australian Proteomic Analysis Facility, W Moore, J Hilton and J Manneken, Aquacore core staff, Australian Regenerative Medicine Institute and Monash University Micromon sequencing facility for technical support. We also thank G Lynch and M Anderson for paper critiques. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-23217-6",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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. https://doi.org/10.1038/s41467-021-23217-6

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.

N1 - Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (PDC, NP: APP1127741, PDC: APP1136567, APP3151883). Australian Research Council Linkage (PDC: LP120100281) in collaboration with Sigma-Aldrich and LIEF Grant (LE150100110). The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. We acknowledge J Callaghan, I Harper, Monash Micro Imaging Facility, J Clark and A Costin, Monash Electron Microscopy Facility, L Kautto, Australian Proteomic Analysis Facility, W Moore, J Hilton and J Manneken, Aquacore core staff, Australian Regenerative Medicine Institute and Monash University Micromon sequencing facility for technical support. We also thank G Lynch and M Anderson for paper critiques. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

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.

UR - https://www.scopus.com/pages/publications/85106231287

U2 - 10.1038/s41467-021-23217-6

DO - 10.1038/s41467-021-23217-6

M3 - Article

C2 - 34012031

AN - SCOPUS:85106231287

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2951

ER -

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

Abstract

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Other files and links

Genetic basis for skeletal muscle formation and regeneration in development and disease

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

A Video-Rate Nanoscopy Facility for Super-Resolution Imaging

AquaCore

Monash Centre for Electron Microscopy (MCEM)

Monash Genomics & Bioinformatics Platform (MGBP)

Cite this

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

Abstract

Access to Document

Other files and links

Projects

Genetic basis for skeletal muscle formation and regeneration in development and disease

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

A Video-Rate Nanoscopy Facility for Super-Resolution Imaging

Equipment

AquaCore

Monash Centre for Electron Microscopy (MCEM)

Monash Genomics & Bioinformatics Platform (MGBP)

Cite this