These authors contributed equally to this work.
Compound loss of muscleblind-like function in myotonic dystrophy
Article first published online: 8 OCT 2013
© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 12, pages 1887–1900, December 2013
How to Cite
Lee, K.-Y., Li, M., Manchanda, M., Batra, R., Charizanis, K., Mohan, A., Warren, S. A., Chamberlain, C. M., Finn, D., Hong, H., Ashraf, H., Kasahara, H., Ranum, L. P. W. and Swanson, M. S. (2013), Compound loss of muscleblind-like function in myotonic dystrophy. EMBO Mol Med, 5: 1887–1900. doi: 10.1002/emmm.201303275
- Issue published online: 2 DEC 2013
- Article first published online: 8 OCT 2013
- Manuscript Accepted: 6 SEP 2013
- Manuscript Revised: 30 AUG 2013
- Manuscript Received: 10 JUL 2013
- National Institutes of Health. Grant Number: AR046799 to M.S.S. and NS058901 to M.S.S. and L.P.W.R.
- myotonic dystrophy;
- RNA-mediated disease
Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.