P.166 - A knock-in mouse model with nonsense dysferlin mutation

Abstract

Mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy with autosomal recessive inheritance pattern. A few mouse models harboring truncating mutations have been in use for the research of the dysferlinopathy. We found nonsense mutations are most common among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which could be mitigated by readthrough strategy. Thus we generated a knock-in mouse with p.Q832* mutation, most frequently found among our dysferlinopathy cases. Mice with homozygous p.Q832* mutation, named dqx, performed poorer on Rotarod and treadmill test than wild type C57BL6 mice and moved less on activity monitoring. On eccentric contraction ex vivo, extensor digitorum longus muscle from dqx tended to break easily on the first few contractions. All these abnormality could successfully be alleviated when the mice were administered with gentamicin for 3 weeks. These results support that readthrough strategy may also be applicable to nonsense dysferlinopathy patients.