P.8.9 Progressive muscular dystrophy in a mouse model of FKRP deficiency

Abstract

Mutations in 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 Muscle Eye Brain Disease. The key defining feature of this group of disorders is the hypoglycosylation of αdystroglycan and its inability to effectively bind extracellular matrix ligands such as laminin α2. We recently generated a mouse with a knock-down in FKRP in the muscle but not the central nervous system (FKRPMD). This mouse shows evidence of muscle fibre degeneration by 6 weeks of age. Despite the hypoglycosylation of α dystroglycan in all muscles examined, the soleus was only mildly affected relative to the other limb muscles. In order to investigate this aspect further we have now undertaken a detailed characterisation of the pattern of muscle involvement in this model, together with a study of the basement membrane changes that accompany the disease process. These analyses should assist in the design of future therapeutic strategies for the FKRP related group of diseases.