Scientists at the Hospital for Sick Children (SickKids) and the University of Las Vegas Nevada (UNLV) have uncovered a genetic link between autism spectrum disorder (ASD) and a rare genetic condition called myotonic dystrophy type 1 (DM1). Headed by Ryan Yuen, PhD, senior scientist in the genetics & genome biology program at SickKids, the study indicates that while ASD has previously been characterized by a loss of gene function, another mechanism may be leading to the social behaviors often observed in individuals with ASD. The team showed that the genetic variation that causes DM1—tandem repeat expansions (TREs) in the DMPK gene—also impacts brain development.
The combined results of their research, including work in mouse models, indicated that the effects of TREs interfere with a critical process called gene splicing, which is essential for gene function. The disruption causes a protein imbalance that can result in mis-splicing of multiple genes involved in brain function, and may explain why some of the social and behavioral outcomes of ASD develop in people with DM1.
“Our findings represent a new way to characterize the genetic development of autism,” said Yuen. “By identifying the molecular pathway behind this connection, we can begin to investigate new approaches to ASD diagnosis and the development of precision therapies that release these proteins back into the genome.”
Yuen and colleagues reported on their study in Nature Neuroscience, in a paper titled, “Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes.”
“Autism spectrum disorder (ASD) is a genetically and clinically heterogeneous neurodevelopmental condition that affects communication and social interactions with restricted interests and repetitive behaviors,” the authors explained. However, the team continued, “despite hundreds of genes known to confer risk for ASD, the molecular mechanisms explaining ASD and comorbid conditions remain elusive.”
DM1 is an inherited condition that causes progressive muscle loss and weakness. And while ASD is present in around 1% of the general population, it is 14 times more likely to develop in people with DM1. But while there is “a clear clinical association” between autism and mytonic dystrophy, the team continued, “a molecular mechanism explaining the manifestation of ASD in DM1-affected individuals is unknown.”
TREs occur when sections of a DNA strand are repeated two or more times, and the likelihood of those repeats causing errors in gene function increases each time. Whole-genome sequencing studies have identified tandem repeat mutations that contribute to ASD risk. One of these is the CTG tandem repeat expansion in the 3′ untranslated region of the DMPK gene, which is known to cause myotonic muscular dystrophy type 1, the authors noted. People with DM1 also have a TRE in the DMPK gene. “The DMPK-CTGexp mutation causes myotonic dystrophy type 1 (DM1), a neuromuscular disease with onset times that span from in utero to late adulthood and highly variable symptom severity,” the team stated.
In 2020, Yuen reported that TREs are genetic contributors to autism, identifying more than 2,588 different places in the genome where TREs were much more prevalent in people with ASD. “A variation really stood out to me that we see in rare neuromuscular disease,” said Łukasz Sznajder, PhD, a research lead and assistant professor at UNLV. “This is how we started connecting the dots. We found a molecular link, or overlap, which we believe is the core of causing autistic symptoms in children with myotonic dystrophy.”
The research team, including collaborators at the University of Florida and Adam Mickiewicz University, found that as the tandem repeat expands in the DMPK gene, its altered RNA binds to a protein that is involved in gene splicing regulation during brain development. This “toxic RNA” depletes the protein and prevents it from binding to other RNA molecules in important areas of the genome, causing a protein imbalance which results in mis-splicing other genes. “… sequestration of MBNL splicing factors by mutant DMPK RNAs with expanded CUG repeats alters the RNA splicing patterns of autism-risk genes during brain development, particularly a class of autism-relevant microexons,” the authors explained. “The loss of MBNL protein function leads to social interaction deficits and restricted responses to novel social and non-social stimuli in mouse models.”
Yuen noted, “TREs are like a sponge that absorbs all these important proteins from the genome. Without this protein, other areas of the genome don’t function properly.”
Both the Yuen Lab and the Sznajder Lab are already exploring whether this mis-splicing is happening in other genes associated with ASD, as well as how their findings could inform precision therapies that release these proteins back into the genome. In summary, the authors wrote, “… we demonstrate a new pathway that produces autistic traits, and propose a model where a gene-specific tandem repeat expansion induces an RNA-mediated gain of function, which leads to altered RNA splicing of multiple ASD-risk genes during brain development, resulting in behavioral traits associated with autism.”
Some of this work is already underway. In 2020, Christopher Pearson, PhD, senior scientist in the genetics & genome biology program at SickKids, identified a molecule that can contract TREs in Huntington’s disease. While more research is needed to identify how this could be applied to other conditions, the investigators remain optimistic that their findings could inform future research and care for DM1, ASD, and other conditions. “Our discovery opens up new therapeutic avenues for ASD by identifying a set of mis-spliced events in ASD-risk genes that could be corrected therapeutically,” they concluded.
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The combined results of their research, including work in mouse models, indicated that the effects of TREs interfere with a critical process called gene splicing, which is essential for gene function. The disruption causes a protein imbalance that can result in mis-splicing of multiple genes involved in brain function, and may explain why some of the social and behavioral outcomes of ASD develop in people with DM1.
“Our findings represent a new way to characterize the genetic development of autism,” said Yuen. “By identifying the molecular pathway behind this connection, we can begin to investigate new approaches to ASD diagnosis and the development of precision therapies that release these proteins back into the genome.”
Yuen and colleagues reported on their study in Nature Neuroscience, in a paper titled, “Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes.”
“Autism spectrum disorder (ASD) is a genetically and clinically heterogeneous neurodevelopmental condition that affects communication and social interactions with restricted interests and repetitive behaviors,” the authors explained. However, the team continued, “despite hundreds of genes known to confer risk for ASD, the molecular mechanisms explaining ASD and comorbid conditions remain elusive.”
DM1 is an inherited condition that causes progressive muscle loss and weakness. And while ASD is present in around 1% of the general population, it is 14 times more likely to develop in people with DM1. But while there is “a clear clinical association” between autism and mytonic dystrophy, the team continued, “a molecular mechanism explaining the manifestation of ASD in DM1-affected individuals is unknown.”
TREs occur when sections of a DNA strand are repeated two or more times, and the likelihood of those repeats causing errors in gene function increases each time. Whole-genome sequencing studies have identified tandem repeat mutations that contribute to ASD risk. One of these is the CTG tandem repeat expansion in the 3′ untranslated region of the DMPK gene, which is known to cause myotonic muscular dystrophy type 1, the authors noted. People with DM1 also have a TRE in the DMPK gene. “The DMPK-CTGexp mutation causes myotonic dystrophy type 1 (DM1), a neuromuscular disease with onset times that span from in utero to late adulthood and highly variable symptom severity,” the team stated.
In 2020, Yuen reported that TREs are genetic contributors to autism, identifying more than 2,588 different places in the genome where TREs were much more prevalent in people with ASD. “A variation really stood out to me that we see in rare neuromuscular disease,” said Łukasz Sznajder, PhD, a research lead and assistant professor at UNLV. “This is how we started connecting the dots. We found a molecular link, or overlap, which we believe is the core of causing autistic symptoms in children with myotonic dystrophy.”
The research team, including collaborators at the University of Florida and Adam Mickiewicz University, found that as the tandem repeat expands in the DMPK gene, its altered RNA binds to a protein that is involved in gene splicing regulation during brain development. This “toxic RNA” depletes the protein and prevents it from binding to other RNA molecules in important areas of the genome, causing a protein imbalance which results in mis-splicing other genes. “… sequestration of MBNL splicing factors by mutant DMPK RNAs with expanded CUG repeats alters the RNA splicing patterns of autism-risk genes during brain development, particularly a class of autism-relevant microexons,” the authors explained. “The loss of MBNL protein function leads to social interaction deficits and restricted responses to novel social and non-social stimuli in mouse models.”
Yuen noted, “TREs are like a sponge that absorbs all these important proteins from the genome. Without this protein, other areas of the genome don’t function properly.”
Both the Yuen Lab and the Sznajder Lab are already exploring whether this mis-splicing is happening in other genes associated with ASD, as well as how their findings could inform precision therapies that release these proteins back into the genome. In summary, the authors wrote, “… we demonstrate a new pathway that produces autistic traits, and propose a model where a gene-specific tandem repeat expansion induces an RNA-mediated gain of function, which leads to altered RNA splicing of multiple ASD-risk genes during brain development, resulting in behavioral traits associated with autism.”
Some of this work is already underway. In 2020, Christopher Pearson, PhD, senior scientist in the genetics & genome biology program at SickKids, identified a molecule that can contract TREs in Huntington’s disease. While more research is needed to identify how this could be applied to other conditions, the investigators remain optimistic that their findings could inform future research and care for DM1, ASD, and other conditions. “Our discovery opens up new therapeutic avenues for ASD by identifying a set of mis-spliced events in ASD-risk genes that could be corrected therapeutically,” they concluded.
The post Altered RNA Splicing of Autism Risk Genes May Link to Behavioral Traits appeared first on GEN - Genetic Engineering and Biotechnology News.