Compound loss of muscleblind-like function in myotonic dystrophy

Kuang Yung Lee, Moyi Li, Mini Manchanda, Ranjan Batra, Konstantinos Charizanis, Apoorva Mohan, Sonisha A. Warren, Christopher M. Chamberlain, Dustin Finn, Hannah Hong, Hassan Ashraf, Hideko Kasahara, Laura P.W. Ranum, Maurice S. Swanson*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

139 Scopus citations


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.

Original languageEnglish
Pages (from-to)1887-1900
Number of pages14
JournalEMBO Molecular Medicine
Issue number12
StatePublished - 12 2013
Externally publishedYes


  • Mbnl1
  • Mbnl2
  • Muscleblind-like
  • Myotonic dystrophy
  • RNA-mediated disease


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