title: A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy.
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.
authors.affiliation: Inserm UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine de Marseille, Université de la Méditerranée, 13005 Marseille, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Krahn
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wein
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.forename: William
authors.initials: W
authors.lastname: Lostal
authors.forename: Sébastien
authors.initials: S
authors.lastname: Courrier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bourg-Alibert
authors.forename: Karine
authors.initials: K
authors.lastname: Nguyen
authors.forename: Christophe
authors.initials: C
authors.lastname: Vial
authors.forename: Nathalie
authors.initials: N
authors.lastname: Streichenberger
authors.forename: Véronique
authors.initials: V
authors.lastname: Labelle
authors.forename: Danielle
authors.initials: D
authors.lastname: DePetris
authors.forename: Christophe
authors.initials: C
authors.lastname: Pécheux
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.forename: Pierre
authors.initials: P
authors.lastname: Cau
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D000073939:Dysferlin; D015316:Genetic Therapy; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000628:therapy
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins