4-Phenylbutyrate restores localization and membrane repair to human dysferlin mutations
Name
1-s2.0-S2589004221016370-main.pdf
Description
Published version
Size
3.11 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Tominaga, Kana
Tominaga, Naoomi
Williams, Eric O
Rufibach, Laura
Schöwel, Verena
Spuler, Simone
Viswanathan, Mohan
Guarente, Leonard P
Date Issued
2022
Journal
iScience
Publisher
Elsevier BV
Citation
Tominaga, Kana, Tominaga, Naoomi, Williams, Eric O, Rufibach, Laura, Schöwel, Verena et al. 2022. "4-Phenylbutyrate restores localization and membrane repair to human dysferlin mutations." iScience, 25 (1).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1016/J.ISCI.2021.103667
