P21 Basement membrane deposition in the skeletal muscle of the FKRPknock-down mouse

Abstract

Abstract Mutations in fukutin-related protein (FKRP) are associated with a clinically heterogenous group of muscular dystrophies, which vary in severity from severe congenital muscular dystrophies, with structural brain and eye involvement, to relatively mild adult-onset limb girdle muscular dystrophies. Central to the pathogenesis of these disorders is the hypoglycosylation of alpha dystroglycan, and defects in basement membrane deposition. We previously generated a mouse model, which has an approximately 80% reduction in levels of FKRP. The newborn brain of this mouse displays a marked reduction in alpha dystroglycan glycosylation and a disturbance in the deposition laminin at the pial basement membrane. In skeletal muscle there is a reduction in both alpha dystroglycan and laminin alpha 2 immunolabelling by the time of birth in the FKRP knock-down compared to controls. There is in addition an associated reduction in muscle mass of the FKRP knock-down, the origin of which is unclear. Here we present our findings with regard to the expression of alpha dystroglycan and its associated ligands laminin alpha 2 and perlecan during muscle development and at birth in the FKRP knock-down relative to wild type controls. Overall our data shows that alpha dystroglycan and its extracellular matrix ligands laminin alpha 2 and perlecan immunolabelling clearly delineate the basement membrane at E15.5 in the mouse. This is a period when secondary myotubes align along the surface of the primaries suggesting that a reduction in the glycosylation of alpha dystroglycan may influence secondary myogenesis.