摘要：SummaryDysferlinopathies are muscular dystrophies caused by recessive loss-of-function mutations in dysferlin (DYSF), a membrane protein involved in skeletal muscle membrane repair. We describe a cell-based assay in which human DYSF proteins bearing missense mutations are quantitatively assayed for membrane localization by flow cytometry and identified 64 localization-defective DYSF mutations. Using this platform, we show that the clinically approved drug 4-phenylbutryric acid (4-PBA) partially restores membrane localization to 25 mutations, as well as membrane repair to cultured myotubes expressing 2 different mutations. Two-day oral administration of 4-PBA to mice homozygous for one of these mutations restored myofiber membrane repair. 4-PBA may hold therapeutic potential for treating a subset of humans with muscular dystrophy due to dysferlin deficiency.Graphical abstractDisplay OmittedHighlights•Most dysferlinopathy patient missense mutants do not localize to the plasma membrane•4-PBA and corr-2b restore membrane localization to patient DYSF missense mutations•4-PBA restores membrane repair to muscle fibers from MMex38 dysferlin mutant mice•Two-day oral treatment with 4-PBA restores mutant DYSF function in mouse muscleMusculoskeletal medicine; Drugs
