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Abstract
Dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in DYSF, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair. Currently, no etiological treatment is available for patients affected with dysferlinopathy. As for other muscular dystrophies, gene therapy approaches based on recombinant adeno-associated virus (rAAV) vectors are promising options. However, because dysferlin messenger RNA is far above the natural packaging size of rAAV, full-length dysferlin gene transfer would be problematic. In a patient presenting with a late-onset moderate dysferlinopathy, we identified a large homozygous deletion, leading to the production of a natural “minidysferlin” protein. Using rAAV-mediated gene transfer into muscle, we demonstrated targeting of the minidysferlin to the muscle membrane and efficient repair of sarcolemmal lesions in a mouse model of dysferlinopathy. Thus, as previously demonstrated in the case of dystrophin, a deletion mutant of the dysferlin gene is also functional, suggesting that dysferlin’s structure is modular. This minidysferlin protein could be used as part of a therapeutic strategy for patients affected with dysferlinopathies.
Footnotes
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↵* These authors contributed equally to this work.
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Citation: M. Krahn, N. Wein, M. Bartoli, W. Lostal, S. Courrier, N. Bourg-Alibert, K. Nguyen, C. Vial, N. Streichenberger, V. Labelle, D. DePetris, C. Pécheux, F. Leturcq, P. Cau, I. Richard, N. Lévy, A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy. Sci. Transl. Med. 2, 50ra69 (2010).
- Copyright © 2010, American Association for the Advancement of Science
