G.P.289

• Published in: Neuromuscular disorders : NMD 2014-10, Vol.24 (9), p.904-904
• Main Authors: Griffin, D, Pozsgai, E, Johnson, R, Grose, W, Heller, K, Mendell, J.R, Sahenk, Z, Rodino-Klapac, L.R
• Format: Article
• Language: English
• Subjects: Neurology
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2014.06.365

Limb girdle muscular dystrophy type 2L (LGMD2L) is caused by mutations in the anoctamin 5 (ANO5) gene. ANO5 encodes a predicted 107 kDa protein containing 8 transmembrane domains and is part of a family that encodes at least 2 calcium-activated chloride channels; however the exact function of ANO5 has yet to be determined. The clinical phenotype overlaps with that of LGMD2B patients having mutations in dysferlin, a gene required for membrane repair. We have developed an ANO5 deficient mouse model (ANO5 KO) for LGMD2L for which no model currently exists. This model is necessary to study disease pathophysiology and test potential therapies. This deficient mouse model has been fundamental to characterize disease pathogenesis, discovering several proteins that may be associated with ANO5, and related functional incapacities. Based on the phenotypic overlap with dysferlin deficiency, we tested whether our ANO5 KO mouse model had a deficit in muscle membrane repair. Following laser induced injury, the flexor digitorum brevis muscles from ANO5 KO mice demonstrated reduced capacity to repair compared to WT strain controls. In addition, we also showed a loss of force compared to wild type mice after mechanical repetitive eccentric contraction in the extensor digitorum longus muscle.. Furthermore, we identified histopathological changes along with mislocalization or reduction in several muscle proteins which are linked and/or secondary to AN05. The ANO5 deficient mouse is novel and represents an important animal model for study of LGMD2L. It is the ideal model to develop proof of principle for gene replacement therapy or pharmacologic approaches and permits studies defining ANO5 function, a critical parameter for therapeutic intervention. The functional deficits we identified provide critical outcome measures to test efficacy of potential therapies and demonstrate feasibility of translation.