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Updated: Jun 17, 2025
A Pipeline to Characterize Structural Heart Defects in the Fetal Mouse
Published on: December 16, 2022
Rescue of Scn5a mis-splicing does not improve the structural and functional heart defects of a DM1 heart mouse model
Larissa Nitschke1, Rong-Chi Hu1,2, Andrew N Miller1
1Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States.
Insights
Myotonic Dystrophy Type 1 (DM1) cardiac dysfunction is not solely due to SCN5A mis-splicing. Reduced SCN5A expression also contributes to DM1 heart disease, suggesting new therapeutic targets for this genetic disorder.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Genetic Disorders
Background:
- Myotonic Dystrophy Type 1 (DM1) is a multisystemic disorder with cardiac complications, a leading cause of mortality.
- Expanded CTG repeats in the DMPK gene cause DM1, leading to RNA toxicity and splicing dysregulation.
- SCN5A mis-splicing, specifically increased exon 6A inclusion, is a known cardiac defect in DM1.
Purpose of the Study:
- To investigate if correcting SCN5A mis-splicing improves cardiac phenotypes in a DM1 mouse model.
- To determine if SCN5A mis-splicing is the sole driver of cardiac deficits in DM1.
- To explore other contributing factors to DM1-related heart disease.
Main Methods:
- Generated mice lacking SCN5A exon 6A to enforce adult SCN5A isoform expression.
- Crossed these mice with a CUG960 DM1 heart mouse model.
- Analyzed cardiac conduction, structure, and SCN5A expression in the generated mouse model and human DM1 heart tissue.
Main Results:
- Correction of SCN5A mis-splicing did not ameliorate cardiac conduction delays or structural changes in the DM1 mouse model.
- SCN5A expression was found to be reduced in heart tissues of both CUG960 mice and DM1-affected individuals.
- These findings indicate that SCN5A mis-splicing is not the exclusive cause of DM1 cardiac pathology.
Conclusions:
- SCN5A mis-splicing alone does not drive DM1 cardiac phenotypes.
- Reduced SCN5A expression represents a significant contributing factor to DM1 heart disease.
- Further research into the role of reduced SCN5A expression may reveal novel therapeutic strategies for DM1 cardiac complications.
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.
