| Popis: |
Dysferlinopathies 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 two 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. Funding Information: The Glenn Foundation for Medical Research, The Jain Foundation, National Institutes of Health R21 Grant 1-R21AR068477-01 (MV, EOW), Grant-in-Aid from Japan Society for the Promotion of Science JSPS 16J40231 (KT), Uehara Memorial Foundation, Japan (KT), Kanzawa Medical Research Foundation Grant-in-Aid (NT), Japan Society for the Promotion of Science Overseas Research Fellowships No. 363 (NT), National Cancer Institute Grant P30-CA14051 Koch Institute. Declaration of Interests: LG is a founder of Elysium Health and Galilei Biosciences. |
