Abstract
Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.
Highlights
Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes
Misregulation of the alternative splicing of the insulin receptor INSR, CLCN1 and Duchenne muscular dystrophy (DMD) mRNAs are associated with the insulin resistance[8], myotonia[9,10,16] and dystrophic process[12], respectively, while alterations of the alternative splicing of BIN1, ryanodine receptor 1 (RYR1), ATP2A1 and CACNA1S may contribute to the skeletal muscle weakness observed in DM13–15
Previous studies[39,40,41] as well as ours indicate that hNav1.5e, the splicing variant of SCN5A found in DM and that contains the fetal exon 6A, possesses a reduced excitability compared with the normal adult splicing form of SCN5A containing the exon 6B
Summary
Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. MBNL and CUGBP1 proteins regulate alternative splicing, and alterations of their functional levels in myotonic dystrophic tissues results in reversion to fetal splicing patterns for several mRNAs, such as the insulin receptor (INSR) Misregulation of the alternative splicing of the insulin receptor INSR, CLCN1 and DMD mRNAs are associated with the insulin resistance[8], myotonia[9,10,16] and dystrophic process[12], respectively, while alterations of the alternative splicing of BIN1, RYR1, ATP2A1 and CACNA1S may contribute to the skeletal muscle weakness observed in DM13–15. Mutations in SCN5A lead to a variety of arrhythmic disorders, including long QT3, progressive and non-progressive cardiac-conduction disease ( known as Lev-Lenegre disease), atrial fibrillation, sick sinus syndrome, Brugada syndrome and numerous overlapping syndromes[19,20,21]
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