title: Translational research and therapeutic perspectives in dysferlinopathies.
abstract: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.
authors.affiliation: University of the Mediterranean, Marseille Medical School, Marseille, France Inserm UMR_S 910 Medical Genetics and Functional Genomics Marseille, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Barthélémy
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wein
authors.forename: Martin
authors.initials: M
authors.lastname: Krahn
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
mesh_terms: D000818:Animals; D000073939:Dysferlin; D015316:Genetic Therapy / Q000379:methods / Q000639:trends; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000628:therapy; D009154:Mutation; D057170:Translational Research, Biomedical / Q000379:methods / Q000639:trends
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins