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


  • K. Tominaga
  • N. Tominaga
  • E.O. Williams
  • L. Rufibach
  • V. Schöwel
  • S. Spuler
  • M. Viswanathan
  • L.P. Guarente


  • iScience


  • iScience 25 (1): 103667


  • 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.