Discovery of novel gene candidate sheds light on autism mechanisms

Autism spectrum disorder (ASD) is a condition affecting the brain's development and often affects the ability of a person to perceive sensory information and social cues and socialize with others. Recent studies have revealed that environmental factors and epigenetic processes, such as DNA methylation, are crucial to the development of ASD. Notably, immune activation and exposure to stress hormones are known to alter neuronal activity in the dorsal raphe (DR, a region of the brain involved in serotonin signaling), contributing to ASD development. Despite this, DNA methylation profiles of the DR in the context of ASD have not been investigated, leaving a critical gap in our understanding of the epigenetic regulation of this brain region and its association with ASD.

In a recent exploratory study, a research team from Japan, led by Professor Hideo Matsuzaki from the Research Center for Child Mental Development, University of Fukui, along with Dr. Keiko Iwata from the School of Pharmaceutical Sciences, Wakayama Medical University, conducted epigenetic profiling on postmortem brain samples of individuals with and without ASD to delve deeper and shed light on this issue. The findings of the study were published in Psychiatry and Clinical Neurosciences on April 24, 2025.

Epigenetic profiling is a process that analyzes chemical modifications on DNA that affect gene regulation. DNA strands can be tagged with chemical markers (like methyl groups), and while these tags don't change the genetic code, they do control how genes are expressed. Using tools like the Infinium HumanMethylation450 BeadChip (Illumina) for DNA methylation profiling and qRT-PCR for gene expression analysis, the researchers conducted genome-wide DNA methylation analysis focused on the DR nucleus, previously under-explored in autism research. Additionally, they also conducted EM-amplicon sequencing to validate the site-specific methylation.

Interestingly, the results of this study revealed extensive DNA methylation abnormalities in the critical genomic regions. In addition, genes like OR2C3 (olfactory receptor gene) and HTR2C (serotonin receptor gene) showed hypermethylation (increase in DNA methylation activity) in ASD brain samples. These changes could be linked to the sensory processing differences and serotonin disruption in patients with ASD. Moreover, they observed hypomethylation in the promoter region of RABGGTB, a gene related to autophagy and synaptic function, which corresponds to its heightened expression.

Elaborating further on these findings, Prof. Matsuzaki says, "RABGGTB is an exciting discovery; it is absent from the current SFARI gene database (a major scientific resource focusing on genes associated with ASD), making it a truly novel candidate for autism." Hinting at the potential of further exploring this gene candidate, he says, "Studying this gene could open new doors to understanding ASD, and perhaps even lead to a future diagnostic biomarker."

Overall, this study sheds light on potential mechanisms underlying ASD, unlocking critical clues for its regulation and adding to the growing understanding of how epigenetic alterations affect neurodevelopmental disorders. Nonetheless, further studies are needed to combine DNA methylation profiling with transcriptome analysis and draw a relation between aberrant DNA methylation and RNA expression. Sharing his closing remarks on this study, Prof. Matsuzaki optimistically says, "Our study provides valuable insights into the molecular landscape of ASD, opening avenues for future diagnosis and therapeutic breakthroughs for autism."