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PubMed2023

Dynamics and variability of transcriptomic dysregulation in congenital myotonic dystrophy during pediatric development.

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by expansion of CTG microsatellite repeats within DMPK. The most severe form, congenital myotonic dystrophy (CDM), has symptom onset at birth due to large intergenerational repeat expansions. Despite a common mutation, CDM individuals present with a distinct clinical phenotype and absence of common DM1 symptoms. Given the clinical divergence, it is unknown if the hallmark of DM1 pathology, dysregulation of alternative splicing (AS) due to sequestration of MBNL proteins within toxic CUG repeat RNAs, contributes to disease throughout pediatric development. To evaluate global transcriptomic dysregulation, RNA-seq was performed on 36 CDM skeletal muscle biopsies ages 2 weeks to 16 years, including two longitudinal samples. Fifty DM1 and adult/pediatric controls were also sequenced as comparative groups. Despite a large CTG expansion and shared age of onset, CDM individuals presented with a heterogenous, MBNL-dependent mis-splicing signature. Estimation of intracellular MBNL concentrations from splicing responses of select events correlated with total spliceopathy and revealed a distinct, triphasic pattern of AS dysregulation across pediatric development. CDM infants (< 2 years) possess severe mis-splicing that significantly improves in early childhood (2-8 years) independent of sex or CTG repeat load. Adolescent individuals (8-16 years) stratified into two populations with a full range of global splicing dysregulation. DMPK expression changes correlated with alterations in splicing severity during development. This study reveals the complex dynamics of the CDM muscle transcriptome and provides insights into new therapeutic strategies, timing of therapeutic intervention, and biomarker development.

Child, Preschool↗

PubMed2025

Pentatricopeptide repeat protein targeting CUG repeat RNA ameliorates RNA toxicity in a myotonic dystrophy type 1 mouse model.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by the expansion of a CTG-triplet repeat in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. It results in the transcription of toxic RNAs that contain expanded CUG repeats (CUGexp). Splicing factors, such as muscleblind-like 1 (MBNL1), are sequestered by CUGexp, thereby disrupting the normal splicing program that is essential for various cellular functions. Pentatricopeptide repeat (PPR) proteins, originally found in plants, regulate RNA in organelles by binding in a sequence-specific manner. Here, we designed PPR proteins that specifically bind to the hexamer of CUG repeat RNAs (CUG-PPRs) and showed that CUG-PPR1 could ameliorate RNA toxicity induced by CUGexp in cell models of DM1. A single systemic recombinant adeno-associated virus (AAV9) vector-mediated gene delivery of CUG-PPR1 demonstrated long-term therapeutic effects on myotonia and restored splicing activity in a mouse model of DM1. These results highlight the potential of PPR molecules to target pathogenic RNA sequences in DM1 and potentially other RNA-mediated disorders.

Animals↗

PubMed2025

Elimination of myotonia improves myopathy in a muscleblind knockout model of myotonic dystrophy.

A cardinal sign of myotonic dystrophy type 1 (DM1) is slow of muscle relaxation after voluntary contraction known as myotonia. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Heralding the onset of weakness, myotonia is often the first symptom of DM1, and raising the possibility that muscle hyperexcitability promotes the subsequent development of myopathy. We used genome editing to test this possibility by deleting the alternatively spliced and frameshift inducing ClC-1 exon 7a (E7a) in the Mbnl1 knockout model of DM1. Although several ClC-1 exons exhibit mis-regulated splicing in DM1, deletion of this single cryptic exon was sufficient to restore ClC-1 function and eliminate myotonia systemically and permanently. As determined by long-read sequencing, deletion of E7a reduced the frequency of other splicing defects in ClC-1 transcripts, likely as a passive consequence of restoring reading frame and nonsense surveillance. Furthermore, we observed significantly improved muscle force generation, fiber-type distribution, and histology, and partial restoration of the muscle transcriptome, including differential gene expression and alternative splicing, in non-myotonic Mbnl1 knockout mice. These results suggest that E7a inclusion is a lynchpin splice event that contributes to skeletal myopathy, highlighting myotonia as a therapeutic target and an outcome of interest in DM1.

Journal Article↗

PubMed2026

Generation of isogenic rescue iPSC lines by targeted CTG-repeat excision for myotonic dystrophy type 1.

An expanded CTG repeat in the Dystrophia Myotonica Protein Kinase (DMPK) gene is associated with myotonic dystrophy type 1 (DM1), an autosomal dominant neuromuscular disorder characterised by progressive muscle weakness, myotonia, cognitive decline, and a variety of other manifestations. Here, we report the generation of isogenic induced pluripotent stem cell (iPSC) lines, derived from patient DM1 iPSC lines carrying varying expanded (CTG)n repeats in DMPK. These gene-edited isogenic iPSC lines, in which the pathogenic repeat has been excised, serve as a reference for assessing DM1-associated phenotypes in relevant differentiated cell types, such as muscle progenitor cells and neurons.

Humans↗

PubMed2026

Treatment updates in myotonic disorders.

Myotonia is delayed muscle relaxation after forceful contraction. It is due to hyperexcitability of the skeletal muscle membrane. It can arise from primary skeletal muscle ion channel dysfunction, involving chloride or sodium channels, but is also a prominent clinical feature in myotonic dystrophies where altered RNA splicing leads to secondary ion channel dysregulation amongst other systemic manifestations. Clinically, myotonia can range from delayed eye opening to a disabling symptom causing impaired mobility, functional difficulty and sometimes pain. It can also be a "hidden disability" with many patients feeling socially embarrassed by "looking healthy", yet being unable to do everyday physical tasks or to do them as effortlessly as their peers. It is a symptom that almost always indicates a genetic diagnosis, although it can occur in acquired conditions, including metabolic and drug-induced causes. To experience myotonia without knowing what it is can be baffling. To receive a genetic diagnosis associated with it can be life changing. Although there is no cure, there are many effective and available symptomatic treatments for myotonia and currently we are in an exciting era of clinical trials for new molecular disease-modifying therapies for myotonic dystrophy type 1. In this review, we consider recent developments in the treatment of myotonic disorders and how they may change clinical practice.

Humans↗

PubMed2026

Alternative splicing dysregulation in CAG repeat expansion diseases.

Alternative splicing of RNA is a highly regulated process that increases the complexity of gene expression, with disruption of splicing leading to significant disruption of cellular function and, ultimately, disease. This spliceopathy is exemplified by myotonic dystrophy type 1, a CTG repeat expansion disease, where dysregulation of alternative splicing drives core disease symptomatology. Recent studies across murine- and patient-derived disease models have demonstrated that similar alternative splicing changes are prevalent in CAG repeat expansion diseases, including Huntington's disease and multiple spinocerebellar ataxias. This review summarizes current knowledge on alternative splicing dysregulation in CAG repeat expansion diseases, highlights potentially disrupted genes and pathways, and discusses mechanisms through which alternative splicing dysregulation may contribute to disease pathogenesis and patient symptomatology.

Humans↗

PubMed2026

Progressive cardiac phenotypes and reduced reversibility from long-term CUGexp RNA expression in a DM1 mouse model.

Myotonic dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUGexp) RNA foci and sequester muscleblind-like (MBNL) RNA-binding proteins. DM1 is multisystemic, with progressive worsening of disease manifestations in affected tissues. Disease progression is attributed to somatic expansion of the CTG repeats with age, resulting in production of CUGexp RNA with enhanced intrinsic toxicity due to increased MBNL sequestration. To determine the degree to which cardiac disease progression can occur independently of repeat expansion, we used a transgenic DM1 mouse model with inducible heart-specific expression of a stable, interrupted 960-CUG-repeat RNA. Sustained CUGexp RNA expression caused progressive cardiac enlargement, contractile dysfunction, conduction delay, myocardial fibrosis, and reduced survival, while MBNL-dependent splicing defects remained static, consistent with the stable repeat length. We also determined the degree of reversibility after different periods of CUGexp RNA expression by shutting off the repeat-containing transgene. Suppression of CUGexp RNA expression rescued cardiac abnormalities, but reversibility declined with longer exposure to the toxic RNA. These findings demonstrate that prolonged expression of stable CUGexp RNA drives progressive cardiac pathology, revealing a mechanism of disease progression in DM1 in addition to somatic expansion.

Animals↗

PubMed2026

Large-scale proteomics profiling of peripheral blood of DM1 patients identifies biomarkers for disease severity and functional capacity.

BackgroundMyotonic Dystrophy Type 1 (DM1), the most common genetic neuromuscular disorder in adults, poses significant challenges for drug development due to its multisystem nature and high clinical variability in symptoms and disease progression. With a growing number of therapies entering clinical trials, this study addresses the urgent need for biomarkers that can serve as surrogate endpoints.MethodsWe profiled 437 serum samples from adult DM1 patients collected at two timepoints of the OPTIMISTIC trial using bottom-up mass spectrometry with data-independent acquisition. Associations between protein expression, the disease-causing CTG-repeat and 25 clinical outcome measures were studied using linear mixed-effect models. All key study findings were validated in an independent cohort of 69 DM1 patients and 10 healthy controls.ResultsOf the 259 identified proteins, 161 showed significant associations with the CTG-repeat length (FDR < 5%). Hypogammaglobulinemia was confirmed and shown to be worse in severely affected patients. A strong proteomic signature was associated with clinical measures of functional capacity, with the 6-Minute Walk Test showing the strongest signal (70 associations, FDR < 5%). These novel associations reveal a compelling link between chronic inflammation and reduced functional capacity. A machine learning algorithm identified a minimal set of 13 proteins robustly reflecting both the underlying genetic defect and functional capacity.ConclusionsDM1 induces a broad disease fingerprint in the serum proteome, predominantly affecting proteins of the immune system. A carefully selected panel of proteins showed the greatest potential to meet the statistical criteria required for surrogate endpoints in clinical trials.

Humans↗