Exon 32 Skipping of Dysferlin Rescues Membrane Repair in Patients' Cells

Florian Barthelemy (1) , Cedric Blouin (2) , Nicolas Wein (1) , Vincent Mouly (3) , Sebastien Courrier (1) , Eugénie Dionnet (1) , Virginie Kergourlay (1) , Yves Mathieu (1) , Luis Garcia (4) , Gillian S. Butler-Browne (3) , Christophe Lamaze (2) , Nicolas Lévy (5) , Martin Krahn (1) , Marc Bartoli (1)

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 CDC - Compartimentation et dynamique cellulaires
3 Centre de recherche en Myologie – U974 SU-INSERM
4 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
5 Département de génétique médicale [Hôpital de la Timone - APHM]

Dysferlinopathies are a family of disabling muscular dystrophies with LGMD2B and Miyoshi myopathy as the main phenotypes. They are associated with molecular defects in DYSF, which encodes dysferlin, a key player in sarcolemmal homeostasis. Previous investigations have suggested that exon skipping may be a promising therapy for a subset of patients with dysferlinopathies. Such an approach aims to rescue functional proteins when targeting modular proteins and specific tissues. We sought to evaluate the dysferlin functional recovery following exon 32 skipping in the cells of affected patients. Exon skipping efficacy was characterized at several levels by use of in vitro myotube formation assays and quantitative membrane repair and recovery tests. Data obtained from these assessments confirmed that dysferlin function is rescued by quasi-dysferlin expression in treated patient cells, supporting the case for a therapeutic antisense-based trial in a subset of dysferlin-deficient patients.

Keywords: Therapy; membrane; neuromuscular diseases; dysferlinopathy; exon-skipping

Domains: Life Sciences [q-bio]; Genetics; Human genetics

Florian Barthelemy, Cedric Blouin, Nicolas Wein, Vincent Mouly, Sebastien Courrier, et al.. Exon 32 Skipping of Dysferlin Rescues Membrane Repair in Patients' Cells. Journal of Neuromuscular Diseases, 2015, 2 (3), pp.281-290. ⟨10.3233/JND-150109⟩. ⟨hal-01662831⟩