MoGen Researchers Uncover Genetic Mechanism Linking Myotonic Dystrophy to Autism

MoGen Researchers Uncover Genetic Mechanism Linking Myotonic Dystrophy to Autism

What if a disease that is known for progressive muscle loss could also help us understand the symptoms of autism? In a significant recent study, researchers from The Hospital for Sick Children (SickKids), the University of Toronto, and the University of Nevada, Las Vegas (UNLV) have uncovered a molecular mechanism that elucidates a surprising link between Myotonic Dystrophy Type 1 (DM1) and Autism Spectrum Disorder (ASD). Their study suggests that RNA mis-splicing, triggered by the presence of a type of genetic variation, tandem repeat expansions (TREs), may underlie the emergence of autism traits in patients with DM1.

The study, published in Nature Neuroscience this year, was co-led by Dr. Ryan Yuen, a co-senior author of the study, principal investigator at SickKids and an associate Professor in the Department of Molecular Genetics at the University of Toronto. In collaboration with researchers from the University of Nevada Las Vegas (led by Dr. Łukasz Sznajder), the Yuen lab’s work sheds new light on how TREs, a class of structural variants understudied due to technical limitations in short-read sequencing, can also disrupt brain development, with exciting implications for treatment. Among the study’s key contributors was PhD candidate Mahreen Khan at the Yuen lab (co-supervised by Dr. Christopher Pearson at MoGen) whose doctoral research focuses on TREs; she is set to defend her dissertation later this year.

The Genetic Variants That Hijack RNA Processing

DM1 is a rare but serious inherited disorder that is caused by TREs, which occur when a short stretch of DNA is repeated many times in a row, specifically of the sequence “CTG” in the DMPK gene, which affects multiple systems including skeletal and cardiac muscle, often leading to progressive muscle loss and weakening. What’s become increasingly clear is that individuals with DM1 are also at greater risk of being diagnosed with autism spectrum disorder (ASD), a neurodevelopmental condition that affects 1 in 36 children and is defined by difficulties with communication, social interactions and repetitive behaviour. Yet, the biological link between the two conditions remained elusive…until now.

At the center of this study was an effort to understand that link at the molecular and mechanistic level. When the CTG repeat expansion in the DMPK gene is transcribed into RNA, it has sites with an unusually high affinity for Muscleblind-like (MBNL) proteins, a family of RNA-binding proteins that are essential for alternative splicing, a fundamental process that allows cells to generate many different versions of a protein from a single gene. In the brain, this process is especially essential as it helps generate the diverse repertoire of proteins needed for neuronal communication and development.  In DM1, however, these expanded RNA repeats bind MBNL proteins, sequestering and trapping them, pulling them away from their regular RNA targets and impairing their regulatory function. This “molecular hijacking” leads to widespread mis-splicing of RNA in various genes.

To understand why DM1 is also associated with autism, Khan analyzed RNA sequencing data from mouse models lacking the MBNL1 and MBNL2 proteins. The team focused on how these proteins regulate splicing and whether their absence led to changes in expression of genes whose disruptions have been tied to autism.

“What we found was that mis-splicing was enriched in genes already associated with autism, particularly those near typical MBNL1 binding sites. The logical conclusion was that sequestration of MBNL1 disrupts its regulatory function, leading to splicing defects in brain- and autism-relevant genes, and that likely contributes to the observed phenotype,” adds Khan.

These findings suggest that this mis-splicing signature is not just a byproduct of the disease but may play a causal role in the emergence of autism-related traits in individuals with DM1.

A Story Years in the Making with Collaboration as Catalyst

The study builds upon years of work by Dr. Yuen and his lab on genetic variation and its relation to disorders, specifically with the motivation to investigate variants in the non-coding region of the genome. That motivation led to his lab’s landmark 2020 discovery that TREs were enriched in the genomes of individuals with autism. By developing new analytical tools, his team identified over 2,500 TREs associated with ASD, many in genes previously not linked to ASD but involved in neuromuscular disorders. Still, identifying these genetic contributors was one of the first steps.

To connect those genomic insights to brain-specific mechanisms, the team turned to their established cross-disciplinary collaborations. Khan, who led key parts of the transcriptomic analysis, reflected on the collaborative nature of the study:

“I think this project really highlighted the impact of collaboration. Everyone brought in different expertise, and together we created a multifaceted story, one that moved from genome to transcriptome to proteome, and finally to functional effect.”

Yuen also credited the team’s success to combining diverse skill sets; mice studies, he noted, were outside his own expertise. “This work could only happen through collaboration,” he emphasized in the interview, and that the project’s success was rooted in having the right people in place to connect the dots from phenotype to molecular mechanism.

Next Steps: Repeat Contraction As A Therapeutic Strategy

Looking ahead, Khan is excited about long-read sequencing, which allows a more detailed investigation of repeat expansions that short-read technologies often miss. She is now using this approach to better characterize known expansions like those in the DMPK gene and to search for novel tandem repeats that may underlie a range of other complex disorders.

“It’s very fulfilling to see the discovery that I made years ago now have a clear mechanistic explanation, and possibly even therapeutic implications, ” says Dr. Yuen, referring to the study’s next steps and his lab’s ongoing collaboration with the Pearson lab on therapeutic strategies.

The mechanistic clarity that the study provides also opens the door to potential targeted therapeutic strategies. In a promising recent study, the Pearson lab demonstrated that a small molecule called naphthyridine-azaquinolone could contract pathogenic CAG repeats in a mouse model of Huntington disease, reducing hallmark disease features. In their continued partnership with the Pearson lab, Dr. Yuen and Khan hope to bring these strategies to bear on the repeat expansions linked not only to autism but also to other complex disorders.

This study was supported by the Azrieli Foundation, the National Institutes of Health (NIH), Myotonic Dystrophy Foundation, Muscular Dystrophy Association, the UNVL startup fund, the University of Florida Centre for Autism and Neurodevelopment, the National Science Centre, Poland, SickKids Research Institute, Brain Canada, the Government of Ontario, the University of Toronto McLaughlin Centre, the Canadian Institutes of Health Research (CIHR), The Petroff Family Foundation, Tribute Communities, The Marigold Foundation and SickKids Foundation.