G.P.6 Assessing the long term expression of LARGE as a potential therapy in a mouse model of LGMD2I

Abstract

Mutations in at least eight genes, including fukutin related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement including Walker–Warburg syndrome. We have now generated a mouse with a knock-down in Fkrp expression in the skeletal muscle, but not the central nervous system (FKRPMD). Analysis of skeletal muscle from this mouse demonstrates hypoglycosylation of α-dystroglycan and a clear muscle pathology by 12weeks of age. Previous work has shown that LARGE overexpression induces hyperglycoyslation of α-dystroglycan in wildtype cells and additionally cells from dystroglycanopathy patients with various primary gene defects, suggesting LARGE could be an important therapeutic approach in these disorders. To test this strategy for FKRP associated disorders, we have crossed our FKRPMD mouse line with a second line overexpressing LARGE. Here we present our histological and physiological evaluation of these mice (FKRPMDLARGE).