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.