Research ArticleMuscular Dystrophy

Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy

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Science Translational Medicine  20 Aug 2014:
Vol. 6, Issue 250, pp. 250ra112
DOI: 10.1126/scitranslmed.3009612

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Proteasome Inhibitors for Patients with Muscular Dystrophy

Many patients affected by muscular dystrophies due to dysferlin deficiency carry pathogenic dysferlin alleles encoding missense mutated proteins, which are degraded by the proteasome. In vitro evidence suggests that such proteins might be functional if salvaged from degradation. Administration of a proteasome inhibitor to three patients harboring a homozygous dysferlin missense mutation led to a marked increase in dysferlin in skeletal muscle and monocytes (Azakir et al.). The salvaged protein became correctly localized to the sarcolemma in muscle biopsies and retained biological activity in patient-derived myoblasts. These results lay the groundwork for long-term studies of proteasomal inhibitors for treating dysferlinopathies and possibly other genetic diseases.