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

Nat Commun. 2021 May 19;12(1):2951. doi: 10.1038/s41467-021-23217-6.

Authors

A J Wood^{1

2}, C H Lin^{3

4}, M Li^{1

2}, K Nishtala^{3

4}, S Alaei^{1

2}, F Rossello^{1

5}, C Sonntag^{1

2}, L Hersey^{1

2}, L B Miles^{1

6}, C Krisp³, S Dudczig^{1

2

7}, A J Fulcher⁸, S Gibertini⁹, P J Conroy^{10

11}, A Siegel^{1

2}, M Mora⁹, P Jusuf^{1

2

7}, N H Packer^{3

4}, P D Currie^{12

13}

Affiliations

¹ Australian Regenerative Medicine Institute (ARMI), Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC, Australia.
² EMBL Australia, Victorian Node, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC, Australia.
³ Biomolecular Discovery and Design Research Centre, Department of Molecular Sciences, Faculty of Science & Engineering, Macquarie University, Sydney, NSW, Australia.
⁴ Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
⁵ University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, VIC, Australia.
⁶ School of Biological Sciences, Monash University, Clayton, VIC, Australia.
⁷ School of Bio-Sciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia.
⁸ Monash Micro Imaging Facility, Monash University, Clayton, VIC, Australia.
⁹ Muscle Cell Biology Laboratory, Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico "Carlo. Besta" Via Temolo 4, Milano, Italy.
¹⁰ Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, VIC, Australia.
¹¹ Monash Antibody Technologies Facility (MATF), Monash University, Clayton, VIC, Australia.
¹² Australian Regenerative Medicine Institute (ARMI), Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC, Australia. peter.currie@monash.edu.
¹³ EMBL Australia, Victorian Node, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC, Australia. peter.currie@monash.edu.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basement Membrane / metabolism
Basement Membrane / pathology
Cell Line
Disease Models, Animal
Fibronectins / metabolism*
Gene Knockout Techniques
Glycosylation
Glycosyltransferases / deficiency
Glycosyltransferases / genetics
Glycosyltransferases / metabolism*
Humans
Male
Muscle, Skeletal / metabolism
Muscle, Skeletal / pathology
Muscular Dystrophies / genetics
Muscular Dystrophies / metabolism*
Muscular Dystrophies / pathology*
Muscular Dystrophies, Limb-Girdle / genetics
Muscular Dystrophies, Limb-Girdle / metabolism
Muscular Dystrophies, Limb-Girdle / pathology
Muscular Dystrophy, Animal / genetics
Muscular Dystrophy, Animal / metabolism*
Muscular Dystrophy, Animal / pathology*
Mutation
Myoblasts, Skeletal / metabolism
Myoblasts, Skeletal / pathology
Pentosyltransferases / deficiency
Pentosyltransferases / genetics
Pentosyltransferases / metabolism*
Phenotype
Zebrafish
Zebrafish Proteins / deficiency
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism*

Substances

Fibronectins
Zebrafish Proteins
FKRP protein, zebrafish
Glycosyltransferases
FKRP protein, human
Pentosyltransferases

Supplementary concepts

Muscular Dystrophy, Limb-Girdle, Type 2I