加拿大多伦多大学Stephen W. Scherer课题组宣布他们研究出X链长链非编码RNA PTCHD1-AS与自闭症的核心特征。相关论文于2026年5月13日发表于国际顶尖学术期刊《自然》杂志上。

该团队检查了ASD患者（9349例）和对照组（8332例）的全基因组测序数据，发现27例男性ASD患者的x染色体微缺失暗示长链非编码RNA PTCHD1-AS是ASD易感性基因（优势比= 2.56,P = 0.01）。通过破坏/删除进化上保守的外显子3创建的两个PTCHD1 -敲除模主题模型显示，雄性小鼠的ASD样特征，包括重复行为增加，社交行为和交流受损，但没有认知共病或ADHD样行为。

在基因敲除小鼠中，海马体依赖的突触功能、复杂的学习和运动活动不受影响。先天核富集母基因PTCHD1-AS从出生后第7天开始在背纹状体中持续表达，背纹状体是一个主要的GABA能脑区，与ASD5有关。多组学分析显示纹状体少突胶质细胞、星形胶质细胞和神经元的转录组学改变影响髓鞘形成和突触可塑性。破坏PTCHD1-AS导致常规蛋白激酶C （cPKC）亚型减少，SRC和GSK-3α/β磷酸化改变，纹状体突触可塑性增强（长期增强和长期抑制）。总之，这些发现暗示纹状体分子和电路水平的失调通过PTCHD1-AS在ASD病因学中。

据了解，在自闭症谱系障碍（ASD）的基因检测中，大约有100个基因或拷贝数变异。已确定的基因是蛋白质编码，相关的表型通常延伸到自闭症的社会行为特征之外，包括认知/医学复杂性和注意缺陷多动障碍（ADHD）。

附：英文原文

Title: An X-linked long non-coding RNA, PTCHD1-AS, and the core features of autism

Author: Bradley, Clarrisa A., Ko, Sangyoon Y., Tian, Meng, Ralph, Liam T., DAbate, Lia, Lee, Jinyeol, Liu, Tianyi, Wang, Junhui, Tidball, Patrick, Mendes, Marla, Fan, Xiaolian, Howe, Jennifer L., Alexandrova, Roumiana, Pellecchia, Giovanna, Casallo, Guillermo, Paton, Tara, Wybenga-Groot, Leanne E., Engchuan, Worrawat, Thiruvahindrapuram, Bhooma, Trost, Brett, de Rijke, Jill, Kadia, Ashish, Jin, Fuzi, Salazar, Nelson Bautista, Diaz-Mejia, J. Javier, MacDonald, Jeffrey R., Deneault, Eric, Ross, P. Joel, Ellis, James, Shum, Carole, Georgiou, John, Rennie, Olivia, Reuter, Miriam S., Hoang, Ny, Sarikaya, Ege, Selvanayagam, Thanuja, Amini, Aeen Ebrahim, Rutherford, Annabel, Rivera-Alfaro, Natalia, Marshall, Christian R., Scala, Marcello, Runke, Cassandra K., Kearney, Hutton M., Christodoulou, John, Francis, David I., Chung, Brian H. Y., Pluciniczak, Jill, Iaboni, Alana, Wigby, Kristen M., Nordahl, Christine W., Amaral, David G., Hudson, Melissa L., Sjaarda, Calvin P.

Issue&Volume: 2026-05-13

Abstract: There are around 100 genes or copy-number variations used in genetic testing for autism spectrum disorder (ASD)1,2. The established genes are protein coding, and the associated phenotypes usually extend beyond sociobehavioural traits seen in autism, including cognitive/medical complexities and attention deficit hyperactivity disorder (ADHD)3,4. We examined whole-genome sequencing data in cases of ASD (9,349) and controls (8,332) and identify 27 male individuals with ASD with X-chromosome microdeletions that implicate the long non-coding RNA PTCHD1-AS as an ASD-susceptibility gene (odds ratio=2.56, P=0.01). Two Ptchd1-as-knockout mouse models, which were created by disrupting/deleting the evolutionarily conserved exon 3, show ASD-like features in male mice, including increased repetitive behaviours and impaired social behaviour and communication without cognitive comorbidities or ADHD-like behaviours. Hippocampus-dependent synaptic function, complex learning and locomotor activity are unaffected in knockout mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from postnatal day 7 onwards in the dorsal striatum, a predominantly GABAergic brain region that is implicated in ASD5. Multi-omics analysis revealed transcriptomic alterations in striatal oligodendrocytes, astrocytes and neurons impacting myelination and synaptic plasticity. Disrupting Ptchd1-as led to reductions in conventional protein kinase C (cPKC) isoforms, altered SRC and GSK-3α/β phosphorylation and enhanced striatal synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit-level dysregulation through PTCHD1-AS in ASD aetiology.

DOI: 10.1038/s41586-026-10515-6

Source: https://www.nature.com/articles/s41586-026-10515-6