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

Authors:

Wood, A. J., Lin, C. H., Li, M., Nishtala, K., Alaei, S., Rossello, F., ... & Currie, P. D.

Keywords:

Glycobiology, Neuromuscular disease, Skeletal muscle

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.

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