The protein dysferlin is abundantly expressed in skeletal and cardiac muscles, where it plays a central role in membrane repair. Mutations in the dysferlin gene (DYSF) engender two autosomal recessive muscular dystrophies: Miyoshi myopathy (MM) and limb-girdle muscular dystrophy type 2B (LGMD-2B). Miyoshi Myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, mostly marked in the distal muscles, especially gastrocnemius and soleus. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with a consequent slow progression.
Mutations in DYSF are thus associated with a wide spectrum of phenotypes, ranging from isolated HyperCPKemia, scapulo-peroneal syndrome, distal myopathy with anterior tibial onset to severe disabilities.
Development of effective therapies remains a great challenge, although different studies demonstrated that transcript rescue was a feasible approach in dystrophinopathies. Thus in some cases, forced exclusion (skipping) of a single exon could restore the reading frame, giving rise to a shorter, but still functional dysferlin protein. In this sense, the combination of gene therapy through the exon-skipping rationale with stem cell protocols represents a valid option.