New Clues to Autism: Epigenetic Study Identifies RABGGTB as a Novel Candidate Gene

May 20, 2025

New Clues to Autism: Epigenetic Study Identifies RABGGTB as a Novel Candidate Gene

Extensive DNA methylation in key brain regions points to RABGGTB as a promising biomarker for autism spectrum disorder

Environmental factors and DNA methylation are known to play a role in the development of autism spectrum disorder (ASD). While environmental factors are known to alter neuronal activity in the dorsal raphe of the brain, researchers have now observed differentially methylated regions in key brain areas as well as heightened expression of RABGGTB¡ªa gene related to autophagy and synaptic function. These findings shed light on the interplay of environmental and genetic factors in ASD.

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.¡±

Researchers from Japan have now identified RABGGTB as a novel autism-linked gene during DNA methylation mapping in the dorsal raphe nuclei of the brain.

Reference
Title of original paper:Genome-wide DNA methylation profiles in the raphe nuclei of patients with autism spectrum disorder
Journal:Psychiatry and Clinical Neurosciences
DOI:10.1111/pcn.13830

About University of Fukui, Japan
The University of Fukui is a preeminent research institution with robust undergraduate and graduate schools focusing on education, medical and science, engineering, and global and community studies. The university conducts cutting-edge research and strives to nurture human resources capable of contributing to society on the local, national, and global levels.

Website: /eng/

About Professor Hideo Matsuzaki from University of Fukui, Japan
Dr. Hideo Matsuzaki is a neuroscientist and serves as a Professor and Center Director at the Research Center for Child Mental Development, University of Fukui, Japan. He obtained a Ph.D. in Medicine from Osaka University in 2003. His research integrates various disciplines to understand the pathophysiology of autism, including metabolic and lipidomic studies, neuroimaging and brain connectivity, analysis of environmental risk factors, and genetic and developmental mechanisms. With °ÄÃŽðɳ_¾º²Ê×ãÇò±È·Ö-ÀºÇòÅ·ÖÞ±­Í¶×¢×¢²áÍƼö than 120 publications and impactful collaborations, he continues to make significant contributions to the field of child mental health.

Funding information
This study was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan to K. I. (19K08041 and 23K07019) and a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan to H. M. (19H03581).

Media contact:
Naoki Tsukamoto
University of Fukui PR center
sskoho-k¡ùad.u-fukui.ac.jp

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