Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies

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. A common feature of these disorders is the variable reduction in the glycosylation of skeletal muscle α-dystroglycan. In order to gain insight into the pathogenesis and clinical variability, we have generated two lines of mice, the first containing a missense mutation and a neomycin cassette, FKRP-NeoTyr307Asn and the second containing the FKRPTyr307Asn mutation alone. We have previously associated this missense mutation with a severe muscle-eye-brain phenotype in several families. Homozygote Fkrp-NeoTyr307Asn mice die soon after birth and show a reduction in the laminin-binding epitope of α-dystroglycan in muscle, eye and brain, and have reduced levels of FKRP transcript. Homozygous FkrpTyr307Asn mice showed no discernible phenotype up to 6 months of age, contrary to the severe clinical course observed in patients with the same mutation. These results suggest the generation of a mouse model for FKRP related muscular dystrophy requires a knock-down rather than a knock-in strategy in order to give rise to a disease phenotype. © The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.