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4-phenylbutyrate restores localization and membrane repair to human dysferlin mutations

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Item Type:Article
Title:4-phenylbutyrate restores localization and membrane repair to human dysferlin mutations
Creators Name:Tominaga, K. and Tominaga, N. and Williams, E.O. and Rufibach, L. and Schöwel, V. and Spuler, S. and Viswanathan, M. and Guarente, L.P.
Abstract: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 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.
Keywords:Musculoskeletal Medicine, Drugs, Animals, Mice
Source:iScience
ISSN:2589-0042
Publisher:Cell Press
Volume:25
Number:1
Page Range:103667
Date:21 January 2022
Official Publication:http://doi.org/10.1016/j.isci.2021.103667
PubMed:View item in PubMed

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