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.
Subject(s)
Fibronectins/metabolism , Glycosyltransferases/metabolism , Muscular Dystrophies/metabolism , Muscular Dystrophies/pathology , Muscular Dystrophy, Animal/metabolism , Muscular Dystrophy, Animal/pathology , Pentosyltransferases/metabolism , Zebrafish Proteins/metabolism , Animals , Basement Membrane/metabolism , Basement Membrane/pathology , Cell Line , Disease Models, Animal , Gene Knockout Techniques , Glycosylation , Glycosyltransferases/deficiency , Glycosyltransferases/genetics , Humans , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Dystrophies/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/metabolism , Muscular Dystrophies, Limb-Girdle/pathology , Muscular Dystrophy, Animal/genetics , Mutation , Myoblasts, Skeletal/metabolism , Myoblasts, Skeletal/pathology , Pentosyltransferases/deficiency , Pentosyltransferases/genetics , Phenotype , Zebrafish , Zebrafish Proteins/deficiency , Zebrafish Proteins/geneticsABSTRACT
INTRODUCTION: Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION: MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.
