Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of CaV1.1 calcium channel
Open Access
- 2 December 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 21 (6), 1312-1324
- https://doi.org/10.1093/hmg/ddr568
Abstract
Myotonic dystrophy type 1 and type 2 (DM1 and DM2) are genetic diseases in which mutant transcripts containing expanded CUG or CCUG repeats cause cellular dysfunction by altering the processing or metabolism of specific mRNAs and miRNAs. The toxic effects of mutant RNA are mediated partly through effects on proteins that regulate alternative splicing. Here we show that alternative splicing of exon 29 (E29) of CaV1.1, a calcium channel that controls skeletal muscle excitation–contraction coupling, is markedly repressed in DM1 and DM2. The extent of E29 skipping correlated with severity of weakness in tibialis anterior muscle of DM1 patients. Two splicing factors previously implicated in DM1, MBNL1 and CUGBP1, participated in the regulation of E29 splicing. In muscle fibers of wild-type mice, the CaV1.1 channel conductance and voltage sensitivity were increased by splice-shifting oligonucleotides that induce E29 skipping. In contrast to human DM1, expression of CUG-expanded RNA caused only a modest increase in E29 skipping in mice. However, forced skipping of E29 in these mice, to levels approaching those observed in human DM1, aggravated the muscle pathology as evidenced by increased central nucleation. Together, these results indicate that DM-associated splicing defects alter CaV1.1 function, with potential for exacerbation of myopathy.Keywords
This publication has 75 references indexed in Scilit:
- The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brainNature Genetics, 2011
- Alternative splicing dysregulation secondary to skeletal muscle regenerationAnnals of Neurology, 2010
- Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channelsPflügers Archiv - European Journal of Physiology, 2010
- Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophyNature Structural & Molecular Biology, 2010
- RNA and DiseaseCell, 2009
- Alternative splicing of RyR1 alters the efficacy of skeletal EC couplingCell Calcium, 2009
- A CaV1.1 Ca2+ Channel Splice Variant with High Conductance and Voltage-Sensitivity Alters EC Coupling in Developing Skeletal MuscleBiophysical Journal, 2009
- Expanded CTG repeats within the DMPK 3′ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophyProceedings of the National Academy of Sciences of the United States of America, 2008
- Increased Steady-State Levels of CUGBP1 in Myotonic Dystrophy 1 Are Due to PKC-Mediated HyperphosphorylationMolecular Cell, 2007
- Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophyProceedings of the National Academy of Sciences of the United States of America, 2006