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Brain Advance Access originally published online on January 20, 2009
Brain 2009 132(2):439-451; doi:10.1093/brain/awn335
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

M. R. Ackroyd1,*, L. Skordis1,*, M. Kaluarachchi1, J. Godwin1, S. Prior1, M. Fidanboylu1, R. J. Piercy1,2, F. Muntoni3 and S. C. Brown1

1 Department of Cellular and Molecular Neuroscience, Hammersmith Hospital, Imperial College, London, UK 2 Department of Veterinary Clinical Sciences, Royal Veterinary College, London, UK 3 Institute of Child Health, UCL, London, UK

Correspondence to: S. C. Brown, Department of Cellular and Molecular Neuroscience, Hammersmith Hospital, Imperial College, London, UK E-mail: s.brown{at}ic.ac.uk

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 {alpha}-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 {alpha}-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.

Key Words: muscular dystrophy; fukutin related protein

Abbreviations: CMD, congenital muscular dystrophies; FKRP, fukutin related protein; ILM, inner limiting membrane; MEB, muscle eye brain disease; WWS, Walker Warburg syndrome

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Received April 15, 2008. Revised October 6, 2008. Accepted November 14, 2008.

*These authors contributed equally to this work.


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