In a major breakthrough, researchers have made significant strides in understanding the genetic underpinnings of autism spectrum disorder (ASD). By studying mice with a frameshift mutation in the KMT2C gene, scientists have gained insight into the behavioral and cognitive impairments associated with ASD.

The study, which involved extensive molecular analysis, revealed an unexpected increase in the expression of genes linked to ASD risk due to KMT2C haploinsufficiency. This finding suggests that there are indirect effects on gene expression that contribute to the development of ASD symptoms.

However, the researchers also discovered a glimmer of hope in the form of a potential therapeutic approach. Treatment with a drug called vafidemstat showed promising results in correcting the abnormalities associated with ASD. The drug was found to ameliorate social deficits and normalize gene expression in mutant mice, indicating its potential as a therapeutic option for ASD and similar conditions.

Autism spectrum disorder is a complex neurodevelopmental condition characterized by repetitive behavior and impaired sociality. It is widely recognized that genetic factors play a role in the development of ASD. Recent research has indicated that genes involved in chromatin modification and gene transcription are particularly relevant to the pathogenesis of ASD.

Among these genes, KMT2C has been identified as being associated with the development of autism and other neurodevelopmental disorders. Previous studies have shown that haploinsufficiency of KMT2C, where only one functional copy of the gene remains, increases the risk of ASD.

To delve deeper into the role of KMT2C in ASD pathogenesis, the researchers created genetically engineered mice with a frameshift mutation that mirrored KMT2C haploinsufficiency. Behavioral analyses of these mutant mice revealed ASD-like symptoms such as reduced sociality, cognitive impairments, inflexibility, and auditory hypersensitivity.

Transcriptomic and epigenetic profiling of the mutant mice unveiled a surprising result: the genes associated with increased ASD risk exhibited higher expression, contrary to expectations. This led the researchers to perform chromatin immunoprecipitation experiments that revealed an overlap between KMT2C and the differentially expressed genes.

Further investigation utilizing single-cell RNA sequencing of newborn mice brains identified undifferentiated radial glial cells as the predominant cell type with altered genes associated with ASD risk. This finding provides valuable information regarding the cell types that contribute to the pathological changes seen in ASD.

The most exciting finding of the study was the potential effectiveness of vafidemstat as a therapeutic agent. This brain-penetrant inhibitor of LSD1, a histone demethylase, demonstrated the ability to improve social deficits and restore the expression levels of differentially expressed genes to normal in the mutant mice.

The implications of this discovery are groundbreaking, challenging the belief that ASD disability may not be curable. It also points towards the potential use of drugs similar to vafidemstat in the treatment of not only ASD but also other psychiatric disorders.

The research opens doors for future studies aimed at strengthening the foundation for pharmacologic treatments of ASD and other neurodevelopmental disorders. The hope is that this breakthrough will pave the way for effective therapies to improve the lives of individuals with ASD and their families.

Professor Kato, one of the lead researchers, concludes, "Our research shows that drugs similar to vafidemstat may be generalizable to multiple categories of psychiatric disorders."

This groundbreaking study, carried out by a team of dedicated scientists, brings us one step closer to understanding the intricate genetic mechanisms underlying autism spectrum disorder.