Abstract
Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood1,2. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the α2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure3, and the missing interaction between muscle basement membrane and the dystrophin–glycoprotein complex (DGC)4 or the integrins5. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction6. Here we show that this mini-agrin—which binds to basement membrane7 and to α-dystroglycan8, a member of the DGC—amends muscle pathology by a mechanism that includes agrin-mediated stabilization of α-dystroglycan and the laminin α5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.
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Acknowledgements
We are grateful to M. Chiquet, S. Kröger, U. Mayer, L. Sorokin and R. Timpl for providing us with antibodies. We thank S. Arber, A. Brancaccio and T. Meier for discussions. M. Dürrenberger and U. Sauder for help in electron microscopy; J.-F. Spetz for DNA injection; M. Willem for providing us with the MCK promoter; and P. Scotton for the help with artwork. Special thanks go to D. Walz for his help in the statistical analysis of the results. This work was supported by grants from the Swiss National Science Foundation (MAR), the Kanton of Basel-Stadt (MAR), the Swiss Foundation for Research on Muscle Diseases (MAR and UM), from the National Institutes of Health (EE), the Novartis Research Foundation (UM), the Deutsche Forschungsgemeinschaft, Aktion Benni and company, and the Ernst und Berta Grimmke-Stiftung (HL).
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Moll, J., Barzaghi, P., Lin, S. et al. An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature 413, 302–307 (2001). https://doi.org/10.1038/35095054
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DOI: https://doi.org/10.1038/35095054
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