A new long non-coding RNA linked to autism
A long‑overlooked stretch of the human genome appears to play a distinct role in shaping the social and stereotypic repetitive behaviours that define Autism Spectrum Disorder (ASD), without affecting learning or other cognitive abilities, according to a major new study published in Nature.
A research has pinpointed PTCHD1-AS, a long non-coding RNA gene on the X chromosome, as a contributor to increased likelihood of ASD in males. Notably, deletions within PTCHD1-AS influence social interaction and repetitive behaviours, while leaving cognition unaffected.
While there are around 100 genes and copy number variations linked to ASD, most encode proteins and are linked to a wide range of developmental outcomes. These findings help distinguish the biological mechanisms underlying Autism’s hallmark behavioral traits from those involved in other brain functions.
“PTCHD1-AS gives us a new entry point to study the biology of ASD, sharpening our understanding of how specific biological pathways relate to key autism traits. This is essential, because no new therapeutics in clinical trials are designed to modulate the main features of ASD,” says the senior author.
Long non‑coding RNAs (lncRNAs), such as PTCHD1-AS, regulate how other genes become turned on and off and until recently have been largely unexplored. Researchers targeted PTCHD1-AS because it sits in a region close to other protein-coding genes that together have been linked to ASD and intellectual disability.
In studying genomic data from over 9,300 individuals in global databases, they discovered that dozens of deletions of the X-linked PTCHD1‑AS were associated with increased ASD susceptibility in males (females have a backup X chromosome).
Follow‑up studies using mouse models developed by the research team further reinforced these findings. Male mice lacking PTCHD1-AS showed changes only in social behavior and increased repetitive actions while they behaved typically in learning, memory and attention tasks.
“Our findings suggest there is a different biology involved with our PTCHD1-AS model compared to other ASD protein-coding models,” says the first author.
What was happening in the brains of these mice? The team found that disrupting PTCHD1‑AS affected “synaptic plasticity,” the brain’s ability to adapt and fine-tune signals in response to activity, inside the striatum, where repetitive behaviours are regulated.
“When we examined gene and protein expression in this area, we saw changes in genes and proteins involved in regulating synaptic plasticity as well as myelination, the process that allows electrical signals to travel faster between neurons. This gives us a molecular pattern we can use for future studies into the biological effect of this non-coding gene in the brain,” adds the author.
They traced these changes to reduced activity of protein kinase C in a specific brain circuit connecting the cortex to the striatum, alongside increases in two forms of synaptic plasticity.
“Through a multi-disciplinary approach combining human genetics, mouse models, multi-omics and electrophysiology, we’ve connected a non-coding gene to measurable changes in brain function,” says the study co-author.
“Together, our research helps clarify how unique alterations in synaptic plasticity relate to the core features of autism.”
The research team notes by linking a specific gene and biological pathway to social and repetitive behaviors, these findings may be relevant across all ASD diagnoses, regardless of clinical complexity.
Next steps for the research include deeper investigation of the molecular, cellular and circuit-level pathways influenced by PTCHD1-AS to identify potential targets driving those core features of ASD and thereby inform future precision therapeutics for those who seek them.
The senior author adds: “Beyond significantly advancing our understanding of Autism as a human condition, the study shows how small changes in DNA can influence complex human behavior.”
“It’s amazing to me how much of our disposition is genetically ‘hardwired,’ even in the traits that shape how we connect and interact,” the author says.
https://www.nature.com/articles/s41586-026-10515-6
https://sciencemission.com/PTCHD1-AS
