Gene Mutation Increases Autism Risk

Summary: Researchers have made significant progress in understanding the genetic underpinnings of autism spectrum disorders. By studying mice with a frameshift mutation in the KMT2C gene, they observed behavioral and cognitive impairments resembling the symptoms of ASD.

Through in-depth molecular analyses, they discovered an unexpected increase in the expression of genes linked to ASD risk due to KMT2C haploinsufficiency, implying indirect effects on gene expression. Remarkably, treatment with the drug vafidemstat has shown promise in correcting these abnormalities, suggesting a potential therapeutic approach for ASD and similar conditions.


  1. Researchers found that a frameshift mutation in the KMT2C gene, leading to haploinsufficiency, models ASD-like symptoms in mice, including reduced sociality and cognitive impairments.
  2. Contrary to expectations, KMT2C haploinsufficiency resulted in increased expression of ASD-associated genes, indicating an indirect mechanism of transcriptomic dysregulation.
  3. Vafidemstat treatment improved social deficits and normalized gene expression in mutant mice, pointing to a promising therapeutic avenue for ASD.

Source: Juntendo University

Autism spectrum disorders (ASD) encompass neurodevelopmental conditions in which patients exhibit repetitive behavior and impaired sociality. Genetic factors have been shown to influence the development of ASD.

Furthermore, recent studies have shown that genes involved in chromatin modification and gene transcription are involved in the pathogenesis of ASD.

Among the many genes involved in this process, the gene KMT2C (lysine methyltransferase 2c), which encodes a catalytic unit of the H3K4 (histone H3 lysine 4) methyltransferase complex, has been identified as being associated with the development of autism and other neurodevelopmental disorders.

They observed that altered genes associated with ASD risk were predominant in undifferentiated radial glial cells. Credit: Neuroscience News

Previous studies have shown that haploinsufficiency (a condition in which, of the two copies of the gene, only one remains functional) of KMT2C is a risk factor for ASD and other neurodevelopmental disorders. However, the molecular mechanism by which loss-of-function mutation in KMT2C leads to these conditions remains unclear.

To fill this knowledge gap, researchers from Juntendo University, RIKEN and the University of Tokyo in Japan aimed to provide answers to these questions in a reference study published in the journal Molecular Psychiatry on March 26, 2024. The research team included Professor Tadafumi Kato from the Department of Psychiatry and Behavioral Sciences at Juntendo University School of Medicine, Dr. Takumi Nakamura and Dr. Atsushi Takata from the RIKEN Center for Science of the brain, as well as Professor Takashi Tsuboi of Graduate School of Arts and Sciences, University of Tokyo.

To get to the bottom of KMT2CIn the pathogenesis of ASD, the team developed and analyzed genetically modified mouse strains (Kmt2c+/fs) having a frameshift mutation that models the KMT2C haploinsufficiency.

They then performed various behavioral analyses, in which they observed that the mutant mice exhibited less sociality, rigidity, auditory hypersensitivity and cognitive impairments, all of which are symptoms linked to ASD.

Next, they performed transcriptomic and epigenetic profiling to understand the basis of the molecular changes observed in the mutant mice. What they found was remarkable: Genes associated with increased risk of ASD had higher expression in these mutant mice.

Dr. Takata exclaims: “It was somewhat unexpected. KMT2C mediates methylation of H3K4, which is thought to activate gene expression, and KMT2C haploinsufficiency is therefore expected to result in reduced expression of target genes.

To gain mechanistic insights into their findings, the researchers performed chromatin immunoprecipitation, a technique for determining the location on DNA where the protein interacts with it.

They found an overlap between KMT2C and differentially expressed genes showing reduced expression, suggesting that KMT2C haploinsufficiency leads to ASD-related transcriptomic changes via an indirect effect on gene expression.

Additionally, to identify cell types that further contribute to the pathological changes observed in the mutant mice, the researchers performed single-cell RNA sequencing of the brains of newborn mice. They observed that altered genes associated with ASD risk were predominant in undifferentiated radial glial cells.

However, no significant changes in cellular composition were observed, implying that transcriptomic dysregulation does not have a serious impact on cell fate.

Finally, the researchers tested the effects of vafidemstat, a brain penetration inhibitor of LSD1 (lysine-specific histone demethylase 1A), which could improve histone methylation abnormalities.

They found that vafidemstat improved social deficits in mutant mice and had an exceptional rescue effect by changing the expression levels of differentially expressed genes to their normal expression level. This finding showed that vafidemstat is a valid drug for mutant mice and can potentially help restore the normal transcriptomic state.

What sets this finding apart is that it challenges the commonly held belief that ASD-related disability cannot be cured and demonstrates the effectiveness of vafidemstat in improving ASD-like phenotypes.

The findings open doors for future research aimed at strengthening the basis for pharmacological treatment of ASD and other neurodevelopmental disorders. Professor Kato concludes: “Our research shows that drugs similar to vafidemstat may be generalizable to several categories of psychiatric disorders. »

About this research news in genetics and autism

Author: Yoshitaka Nakashima
Source: Juntendo University
Contact: Yoshitaka Nakashima – Juntendo University
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor” by Tadafumi Kato et al. Molecular Psychiatry


Transcriptomic dysregulation and autism-like behaviors Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor

Recent studies have consistently demonstrated that chromatin regulation and gene transcription play a central role in the pathogenesis of neurodevelopmental disorders.

Among the many genes involved in these pathways, KMT2Cencoding one of six histone H3 lysine 4 (H3K4) methyltransferases known in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD ) and the phenotypic spectrum of Kleefstra syndrome.

However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated.

To address this issue, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation. Kmt2c (Kmt2c+/fs mouse) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autism-like behaviors such as deficits in sociality, flexibility, and working memory, demonstrating their face validity as a model of ASD.

To investigate the molecular basis of the observed abnormalities, we performed transcriptomic analysis of their adult brains and found that ASD risk genes were specifically enriched in upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP -seq were significantly co. -localized with downregulated genes, suggesting an important role for putative indirect effects of Kmt2c haploinsufficiency.

We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved information at an earlier stage.

By integrating results from ASD exome sequencing, genome-wide associations, and postmortem brain studies to characterize DEGs in each cell group, we discovered strong transcriptomic changes associated with ASD in radial glia and immature neurons, with no obvious bias toward upregulated or downregulated DEGs. In contrast, there was no significant change in cellular composition.

Finally, we explored potential therapeutic agents and demonstrated that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor effective in other models of neuropsychiatric/neurodevelopmental disorders, improves social impairments but not memory of work in adults. Kmt2c+/fs mouse.

Intriguingly, vafidemstat administration was shown to modify the vast majority of DEGs in the direction of normalization of transcriptomic abnormalities in mutant mice (94.3 and 82.5% of DEGs significantly upregulated and downregulated). decline, respectively). P. <2.2 × 10−16binomial test), which could be the molecular mechanism underlying behavioral rescue.

In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates cell type-resolved molecular alterations due to Kmt2chaploinsufficiency, and demonstrates the effectiveness of an LSD1 inhibitor that could be generalizable to several categories of psychiatric disorders as well as a better understanding of its presumed mechanisms of action.

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