Summary: Researchers identified a specific \u201clong non-coding\u201d RNA gene, PTCHD1-AS, that influences the core behavioral traits of Autism Spectrum Disorder (ASD).<\/p>\n
The study reveals that deletions in this X-linked gene specifically impact social interaction and repetitive behaviors in males without affecting cognitive abilities like learning or memory. This discovery helps isolate the biological mechanisms of autism\u2019s hallmark traits from other developmental functions.<\/p>\n
Key Research Findings<\/p>\n
A \u201cNon-Coding\u201d Discovery: PTCHD1-AS belongs to a class of genes called long non-coding RNAs (lncRNAs), which act as regulators that turn other genes on and off. This distinguishes it from the ~100 other ASD-linked genes that primarily encode proteins.Behavioral Specificity: Deletions of PTCHD1-AS on the X chromosome were found to increase ASD susceptibility in males. In mouse models, those lacking this gene showed typical attention and memory but exhibited increased repetitive actions and altered social behavior.Striatal Circuitry: The team pinpointed the striatum, the brain region responsible for regulating repetitive behaviors, as the primary site of impact.Synaptic Plasticity: Disrupting PTCHD1-AS affected the brain\u2019s ability to fine-tune signals (synaptic plasticity) and the process of myelination, which allows electrical signals to travel faster between neurons.The Protein Kinase C Link: The behavioral changes were traced to reduced activity of protein kinase C in a specific circuit connecting the cortex to the striatum.<\/p>\n
Source: Hospital for Sick Children<\/p>\n
A\u202flong\u2011overlooked\u202fstretch of the human genome\u202fappears to play\u202fa distinct role in shaping the social and stereotypic repetitive\u202fbehaviours\u202fthat define Autism Spectrum Disorder (ASD),\u202fwithout affecting learning or other cognitive abilities,\u202faccording to a major new study published in\u202fNature.\u202f\u00a0<\/p>\n
A research team\u202fled by\u202fThe Hospital for Sick Children (SickKids)\u202fhas pinpointed\u00a0PTCHD1-AS,\u00a0a\u202flong non-coding RNA gene on the X chromosome,\u202fas a contributor to increased\u00a0likelihood\u00a0of ASD in males.\u202fNotably,\u202fdeletions\u202fwithin\u00a0PTCHD1-AS\u00a0influence social\u00a0interaction\u00a0and repetitive\u202fbehaviours, while leaving cognition unaffected.\u202f\u202f\u00a0<\/p>\n
While there are around 100 genes and copy number variations linked to ASD, most encode\u00a0proteins\u00a0and\u00a0are linked to a wide range of developmental outcomes. These findings help distinguish the biological mechanisms underlying Autism\u2019s hallmark\u202fbehavioural\u202ftraits from those involved in other brain functions.\u202f\u00a0<\/p>\n
\u201cPTCHD1-AS\u202fgives us a new entry point to study the biology of ASD,\u202fsharpening our understanding\u00a0of how specific biological pathways relate to key autism traits. This is essential, because no new therapeutics in clinical trials are designed to\u202fmodulate\u202fthe\u202fmain features\u202fof ASD,\u201d\u202fsays senior author Dr.\u202fStephen Scherer, Senior Scientist,\u202fGenetics & Genome Biology\u202fand Chief of Research at SickKids, and Director of the McLaughlin Centre at the University of Toronto.\u202f\u00a0<\/p>\n
A non-coding gene with a distinct role\u202f\u00a0<\/p>\n
Roughly one\u202fin 50 children and youth in Canada\u202fhave\u00a0ASD. Despite the diverse ways they experience the condition,\u202fchanges in\u202fsocial interaction and\u00a0repetitive\u202fbehaviours\u00a0are\u00a0common\u00a0across the spectrum.\u202f\u202f\u00a0<\/p>\n
Long\u202fnon\u2011coding\u202fRNAs (lncRNAs), such as\u202fPTCHD1-AS,\u202fregulate\u202fhow other\u00a0genes\u00a0become\u00a0turned\u00a0on and off\u202fand until recently have\u00a0been\u00a0largely\u00a0unexplored.\u00a0Researchers\u00a0targeted\u00a0PTCHD1-AS\u202fbecause it\u202fsits in a region close to other protein-coding genes\u00a0that\u00a0together\u00a0have\u202fbeen linked to ASD\u202fand\u202fintellectual disability.\u202f\u202f\u00a0<\/p>\n
In studying genomic data from over 9,300\u202findividuals\u202fin global\u202fdatabases, they discovered that\u202fdozens of\u202fdeletions\u202fof\u202fthe X-linked\u202fPTCHD1\u2011AS\u00a0were associated with increased ASD\u202fsusceptibility\u202fin males\u202f(females have a backup X chromosome).\u202f\u202f\u00a0<\/p>\n
Follow\u2011up\u202fstudies using mouse models developed by\u202fthe research team further\u202freinforced these findings.\u202fMale mice lacking\u00a0PTCHD1-AS\u202fshowed\u202fchanges\u202fonly\u202fin social\u00a0behaviour\u00a0and increased repetitive actions\u202fwhile they behaved\u00a0typically\u00a0in\u202flearning,\u202fmemory\u202fand attention\u202ftasks.\u202f\u00a0<\/p>\n
\u201cOur findings suggest there is a different biology involved with our\u202fPTCHD1-AS\u00a0model\u00a0compared to other ASD protein-coding models,\u201d says Dr. Lisa Bradley, first author and Research Associate in\u202fThe Centre for Applied Genomics (TCAG)\u202fat SickKids.\u202f\u202f\u00a0<\/p>\n
How\u202fPTCHD1-AS\u202finfluences\u202fbrain circuitry\u202f\u00a0<\/p>\n
What was happening in the brains of these mice?\u202fThe team found\u00a0that\u00a0disrupting\u00a0PTCHD1\u2011AS\u00a0affected\u202f\u201csynaptic plasticity,\u201d\u202fthe brain\u2019s ability to adapt\u202fand fine-tune\u202fsignals in response to activity,\u202finside the\u202fstriatum,\u202fwhere repetitive\u202fbehaviours\u202fare\u202fregulated.\u202f\u202f\u00a0<\/p>\n
\u201cWhen 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,\u201d adds Bradley.\u202f\u00a0<\/p>\n
They\u202ftraced these changes to reduced activity of protein kinase C in\u202fa specific brain circuit connecting the cortex to the striatum, alongside increases\u202fin two forms of synaptic plasticity.\u202f\u00a0<\/p>\n
\u201cThrough a multi-disciplinary approach combining human genetics, mouse models, multi-omics\u00a0and electrophysiology,\u202fwe\u2019ve connected\u202fa non-coding gene to measurable\u00a0changes\u202fin brain function,\u201d says study\u202fco-author Dr. Graham Collingridge, Senior\u00a0Investigator\u00a0at Lunenfeld-Tanenbaum Research Institute, Sinai Health\u202fand Director of the Tanz Centre for Research in Neurodegenerative Diseases\u202fand Professor in the Department of Physiology at\u202fTemerty\u202fFaculty of\u202fMedicine\u202fat the University of Toronto.\u202f\u202f\u00a0<\/p>\n
\u201cTogether, our research helps\u202fclarify how\u202funique alterations in synaptic plasticity\u202frelate to\u202fthe core features of\u202fautism.\u201d\u202f\u202f\u00a0<\/p>\n
Toward\u202fa\u202fmore precise understanding of ASD biology\u202f\u00a0<\/p>\n
The research team notes by linking a specific gene and biological pathway to social and repetitive\u202fbehaviours, these findings may be relevant across all ASD diagnoses, regardless of clinical complexity.\u202f\u00a0<\/p>\n
Next steps for the research include deeper\u202finvestigation\u202fof\u202fthe\u202fmolecular,\u202fcellular\u202fand circuit-level pathways influenced by\u202fPTCHD1-AS\u00a0to\u202fidentify\u202fpotential\u202ftargets\u202fdriving\u00a0those\u00a0core\u202ffeatures of ASD\u202fand thereby inform\u202ffuture precision therapeutics\u202ffor those who seek them.\u202f\u202f\u00a0<\/p>\n
Scherer, who is also a\u202fProfessor\u202fin the Department of Molecular Genetics at\u00a0Temerty\u00a0Faculty of Medicine at University of Toronto,\u202fadds: \u201cBeyond significantly advancing our understanding of\u202fAutism as a human condition, the study shows how small changes in DNA can\u202finfluence complex human\u202fbehaviour.\u201d\u202f\u00a0<\/p>\n
\u201cIt\u2019s\u202famazing\u202fto me\u202fhow much of our\u202fdisposition\u202fis\u202fgenetically \u2018hardwired,\u2019\u202feven in the traits that shape how we connect and interact,\u201d\u202fhe says.\u202f\u00a0<\/p>\n
Funding: The\u202fstudy was funded\u202fthrough support from\u202fAutism Speaks,\u202fAutism Science Foundation,\u202fCanada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), Genome Canada and Ontario Genomics, the Government of Ontario, Ontario Brain Institute, the Province of Ontario Neurodevelopment Disorders (POND) Network,\u202fSimons Foundation Autism Research Initiative, University of Toronto McLaughlin Centre\u202fand SickKids Foundation.\u202f\u00a0<\/p>\n
Key Questions Answered:Q: Why does this gene specifically affect males?<\/p>\n
A: PTCHD1-AS is located on the X chromosome. Because males have only one X chromosome, a deletion in this gene has a direct impact. Females have a second \u201cbackup\u201d X chromosome that can often compensate for the loss.<\/p>\n
Q: How can a gene affect \u201csocial skills\u201d but not \u201cintelligence\u201d?<\/p>\n
A: This is the major breakthrough of the study. Most known autism genes affect a wide range of brain functions, including cognition. PTCHD1-AS is unique because it specifically regulates the brain circuits in the striatum responsible for social and repetitive behaviors, leaving the centers for learning and memory intact.<\/p>\n
Q: Will this lead to new treatments for autism?<\/p>\n
A: Currently, no clinical trials are designed to modulate the core features of ASD. By identifying the specific molecular pathway involving protein kinase C and synaptic plasticity, researchers have a \u201cnew entry point\u201d to develop precision therapeutics that target the core traits of autism directly.<\/p>\n
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this genetics and autism research news<\/p>\n
Author:\u00a0Jelena Djurkic<\/a>
Source:\u00a0Hospital for Sick Children<\/a>
Contact:\u00a0Jelena Djurkic \u2013 Hospital for Sick Children
Image:\u00a0The image is credited to Neuroscience News<\/p>\n