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., Tominaga, N., Williams, E.O., Rufibach, L., Schöwel, V., Spuler, S., 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:	https://doi.org/10.1016/j.isci.2021.103667
PubMed:	View item in PubMed

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