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

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 alpha -dystroglycan (alpha -DG). Although this modification is critical for extracellular matrix attachment, alpha -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. FKRP mutations cause muscular dystrophies with varied clinical presentations. The target of FKRP is alpha -dystroglycan, but here the authors show that FKRP also directs sialylation of fibronectin, a process that is essential for recruitment o collagen to the muscle basement membrane.

Automated summary

Mutations in FKRP cause muscular dystrophies with diverse clinical presentations. In addition to targeting alpha-dystroglycan, FKRP also guides the sialylation of fibronectin, which is essential for collagen recruitment to the muscle basement membrane.