A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy.
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.
Krahn
Martin
M
Inserm UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine de Marseille, Université de la Méditerranée, 13005 Marseille, France.
Wein
Nicolas
N
Bartoli
Marc
M
Lostal
William
W
Courrier
Sébastien
S
Bourg-Alibert
Nathalie
N
Nguyen
Karine
K
Vial
Christophe
C
Streichenberger
Nathalie
N
Labelle
Véronique
V
DePetris
Danielle
D
Pécheux
Christophe
C
Leturcq
France
F
Cau
Pierre
P
Richard
Isabelle
I
Lévy
Nicolas
N
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
C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins