LIMB-GIRDLE MUSCULAR DYSTROPHY I: P.6Functional recovery by readthrough therapy in a knock-in mouse model with nonsense dysferlin mutation

Abstract

Defects in dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy. Nonsense mutations have been reported to be most common among Korean patients with dysferlinopathy. More than half of the patients have at least one nonsense allele in dysferlin. Readthrough by ataluren is a promising strategy to overcome nonsense mutation, in use for the nonsense-mediated Duchenne muscular dystrophy. We generated a knock-in mouse with p.Q832* mutation, most frequently found among our dysferlinopathy cases. Mice with homozygous p.Q832* mutation lost dysferlin expression at sarcolemma. It performed worse on the Rotarod and forelimb grip test than wild type C57BL6 mice and moved less on activity monitoring. On eccentric contraction ex vivo, extensor digitorum longus muscle from these mice tended to break easily. These abnormalities could successfully be alleviated when the mice were orally administered with ataluren in liquid. Furthermore, ataluren decreased the number of damaged muscle, fiber size variation and serum creatine kinase level. This results support that readthrough strategy with ataluren will also be applicable to patients with nonsense dysferlin mutation.