A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Science Translational Medicine Année : 2010

A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy

William Lostal
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Nathalie Bourg-Alibert
Christophe Vial
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Christophe Pecheux
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Isabelle Richard

Résumé

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.
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Dates et versions

hal-01610037 , version 1 (13-12-2017)

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Martin Krahn, Nicolas Wein, Marc Bartoli, William Lostal, Sebastien Courrier, et al.. A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy. Science Translational Medicine, 2010, 2 (50), ⟨10.1126/scitranslmed.3000951⟩. ⟨hal-01610037⟩
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