Language
English
Publication Date
10-7-2024
Journal
Human Molecular Genetics
DOI
10.1093/hmg/ddae117
PMID
39126705
PMCID
PMC11458005
PubMedCentral® Posted Date
8-11-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant multisystemic disorder for which cardiac features, including conduction delays and arrhythmias, are the second leading cause of disease mortality. DM1 is caused by expanded CTG repeats in the 3' untranslated region of the DMPK gene. Transcription of the expanded DMPK allele produces mRNAs containing long tracts of CUG repeats, which sequester the Muscleblind-Like family of RNA binding proteins, leading to their loss-of-function and the dysregulation of alternative splicing. A well-characterized mis-regulated splicing event in the DM1 heart is the increased inclusion of SCN5A exon 6A rather than the mutually exclusive exon 6B that normally predominates in adult heart. As previous work showed that forced inclusion of Scn5a exon 6A in mice recapitulates cardiac DM1 phenotypes, we tested whether rescue of Scn5a mis-splicing would improve the cardiac phenotypes in a DM1 heart mouse model. We generated mice lacking Scn5a exon 6A to force the expression of the adult SCN5A isoform including exon 6B and crossed these mice to our previously established CUG960 DM1 heart mouse model. We showed that correction Scn5a mis-splicing does not improve the DM1 heart conduction delays and structural changes induced by CUG repeat RNA expression. Interestingly, we found that in addition to Scn5a mis-splicing, Scn5a expression is reduced in heart tissues of CUG960 mice and DM1-affected individuals. These data indicate that Scn5a mis-splicing is not the sole driver of DM1 heart deficits and suggest a potential role for reduced Scn5a expression in DM1 cardiac disease.
Keywords
Animals, NAV1.5 Voltage-Gated Sodium Channel, Mice, Disease Models, Animal, Myotonic Dystrophy, Alternative Splicing, Exons, Humans, Myocardium, Myotonin-Protein Kinase, Heart, RNA Splicing, myotonic dystrophy, alternative splicing, repeat expansion disorders, SCN5A, cardiac conduction
Published Open-Access
yes
Recommended Citation
Nitschke, Larissa; Hu, Rong-Chi; Miller, Andrew N; et al., "Rescue of Scn5a Mis-Splicing Does Not Improve the Structural and Functional Heart Defects of a DM1 Heart Mouse Model" (2024). Faculty and Staff Publications. 4028.
https://digitalcommons.library.tmc.edu/baylor_docs/4028