Phenylbutyrate restores dysferlin localization and membrane repair in cellular and animal models of dysferlinopathies

Missense mutations account for 30 to 40% of abnormalities responsible for dysferlinopathy. They generate abnormal, misfolded and unstable dysferlins, which can result in an absence of dysferlin at the plasma membrane in immunocytochemistry.

An international team has developed a technique based on flow cytometry to measure the amount of dysferlin localized to the cell membrane and evaluated the effects of phenylbutyrate on this localization.

  • Among 113 missense mutations identified in people with dysferlinopathy listed in the Jain Foundation Registry, 64 generated in a quantity of dysferlin localized to the cell membrane less than 25% of the normal level.
  • Cells with these 64 missense mutations were treated with 4-phenylbutyric acid (4-BPA) proposed as a chaperone molecule in diseases involving misfolded proteins. For 25 of these mutations, this increased:
    • production of dysferlin more than 25% of normal;
    • and, in some cases, the amount of dysferlin localized to the membrane, without this reaching the levels of a normal dysferlin.
  • Administration of 4-PBA for 48 hours to DYSFL1341P human missense mutation model mice restores:
    • partially localizes dysferlin to the membrane and restores normal membrane repair activity. Further studies are needed to assess the effectiveness of 4-PBA in animal models of other human dysferlin mutations, as well as in cells from people with dysferlin.

Further studies are needed to assess the effectiveness of 4-PBA in animal models of other human dysferlin mutations, as well as in cells from people with dysferlin.

 

4-Phenylbutyrate restores localization and membrane repair to human dysferlin mutations. Tominaga K, Tominaga N, Williams EO, Rufibach L, Schöwel V, Spuler S, Viswanathan M, Guarente LP. iScience. 2021 Dec 20;25(1):103667.