Proteasome inhibitor salvages messense mutated dysferlin in muscular dystrophy patients


Multiple inherited muscular dystrophies, such as limb-girdle muscular dystrophy type 2B, are resulted from mutations in the dysferlin gene (DYSF), cause deficiency in the muscle transmembrane protein dysferlin. Previous studies showed proteasome is responsible for the degradation of dysferlin, and the missense mutations in DYSF alleles may salvage the protein from degradation. In this study, Azakir et al. demonstrated proteasome inhibitor is able to increase the expression of messense mutated dyferlin, and restores the membrane resealing capacity of myoblasts. The article was published in Science Translational Medicine.


It has been shown that the inhibition of the proteasomal system can significantly increase the expression of dysferlin with an Arg555Trp missense mutation in patient-derived cultured myoblasts. This missense mutated protein salvaged from proteasome was functional suggested by the restoration of plasma membrane resealing and impaired myotube formation in vitro. To further investigated this strategy in vivo, Azakir et al. administered FDA-approved proteasome inhibitor, brotezomib, to three dysferlin-deficient muscular dystrophy patients though either intravenous or subcutaneous injection. The three patients carried homozygous for the Arg555Trp DYSF missense mutation. They measured dysferlin expression and found bortezomib increased missense mutated dysferlin in skeletal muscle tissue and blood monocytes in vivo. Histological sections showed missense mutated dysferlin correctly located in the sarcolemma of muscle fibers. These findings prove the effects of proteasome inhibitor on increase missense mutated dysferlin in vivo, and suggest a potential therapeutic strategy may facilitate the recovery of patients with muscular dystrophies.


Sci Transl Med. 2014 Aug 20;6(250):250ra112.

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