Kostyanovskaya Elina, Lasser Micaela C, Wang Belinda, Schmidt James, Bader Ethel, Buteo Chad, Arbelaez Juan, Sindledecker Aria Rani, McCluskey Kate E, Castillo Octavio, Wang Sheng, Dea Jeanselle, Helde Kathryn A, Graglia J Michael, Brimble Elise, Kastner David B, Ehrlich Aliza T, State Matthew W, Willsey A Jeremy, Willsey Helen Rankin
Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA.
SynGap Research Fund, Mill Valley, CA.
bioRxiv. 2025 Jan 14:2024.12.05.626924. doi: 10.1101/2024.12.05.626924.
Hundreds of high-confidence autism genes have been identified, yet the relevant etiological mechanisms remain unclear. Gene ontology analyses have repeatedly identified enrichment of proteins with annotated functions in gene expression regulation and neuronal communication. However, proteins are often pleiotropic and these annotations are inherently incomplete. Our recent autism functional genetics work has suggested that these genes may share a common mechanism at the cilium, a membrane-bound organelle critical for neurogenesis, brain patterning, and neuronal activity-all processes strongly implicated in autism. Moreover, autism commonly co-occurs with conditions that are known to involve ciliary-related pathologies, including congenital heart disease, hydrocephalus, and blindness. However, the role of autism genes at the cilium has not been systematically investigated. Here we demonstrate that autism proteins spanning disparate functional annotations converge in expression, localization, and function at cilia, and that patients with pathogenic variants in these genes have cilia-related co-occurring conditions and biomarkers of disrupted ciliary function. This degree of convergence among genes spanning diverse functional annotations strongly suggests that cilia are relevant to autism, as well as to commonly co-occurring conditions, and that this organelle should be explored further for therapeutic potential.
数百个高置信度的自闭症相关基因已被确定，但相关的病因机制仍不清楚。基因本体分析多次发现，具有注释功能的蛋白质在基因表达调控和神经元通讯方面存在富集现象。然而，蛋白质往往具有多效性，而且这些注释本质上是不完整的。我们最近关于自闭症的功能遗传学研究表明，这些基因可能在纤毛处共享一种共同机制，纤毛是一种对神经发生、脑模式形成和神经元活动至关重要的膜结合细胞器——所有这些过程都与自闭症密切相关。此外，自闭症常与已知涉及纤毛相关病理的疾病同时出现，包括先天性心脏病、脑积水和失明。然而，自闭症相关基因在纤毛处的作用尚未得到系统研究。在这里，我们证明，跨越不同功能注释的自闭症相关蛋白质在纤毛的表达、定位和功能上存在趋同现象，并且这些基因中存在致病变异的患者具有与纤毛相关的并发疾病以及纤毛功能紊乱的生物标志物。跨越不同功能注释的基因之间的这种趋同程度强烈表明，纤毛与自闭症以及常见的并发疾病相关，并且应该进一步探索这个细胞器的治疗潜力。
