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.
Highlights
The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes
Fkrp mutant larvae possessed a significant loss of (IIH6) reactivity, a marker of glycosylated dystroglycan, fukutin-related protein (FKRP)’s canonical target. This loss of immunoreactivity could not be attributed to an overall loss of dystroglycan protein, or loss of dystroglycan’s core-binding partner, Laminin, whose deposition was significantly increased at the muscle basement membrane in homozygous mutant fkrp larvae (Extended Data Fig. 2)
The phenotypes of fkrp−/− and dag1−/− mutants were compared for muscle structure and integrity defects at 3 and 5 days post fertilisation, a period during which progressive muscular dystrophy and muscle basement membrane (MBM) attachment defects were evident in our previously generated zebrafish models of muscular dystrophy[11,12,13]
Summary
The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. 1–3) to that which presents in α-dg (dag1−/−) mutants, the canonical target of FKRP glycosylation[10], novel modes of FKRP function could be identified To perform these analyses, the phenotypes of fkrp−/− and dag1−/− mutants were compared for muscle structure and integrity defects at 3 and 5 days post fertilisation (dpf), a period during which progressive muscular dystrophy and muscle basement membrane (MBM) attachment defects were evident in our previously generated zebrafish models of muscular dystrophy[11,12,13].
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