Yang Kang, Zhang Tian, Niu Ruize, Zhao Liyang, Cheng Zhonghe, Li Jun, Wang Lifang
National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, China.
Affiliated Mental Health Center & Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Front Genet. 2024 Sep 23;15:1483574. doi: 10.3389/fgene.2024.1483574. eCollection 2024.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by impairments in social interaction, communication, and repetitive behaviors. Emerging evidence suggests that the insulin-like growth factor (IGF) signaling pathway plays a critical role in ASD pathogenesis; however, the precise pathogenic mechanisms remain elusive. This study utilizes multi-omics approaches to investigate the pathogenic mechanisms of ASD susceptibility genes within the IGF pathway. Whole-exome sequencing (WES) revealed a significant enrichment of rare variants in key IGF signaling components, particularly the IGF receptor 1 (IGF1R), in a cohort of Chinese Han individuals diagnosed with ASD, as well as in ASD patients from the SFARI SPARK WES database. Subsequent single-cell RNA sequencing (scRNA-seq) of cortical tissues from children with ASD demonstrated elevated expression of IGF receptors in parvalbumin (PV) interneurons, suggesting a substantial impact on their development. Notably, IGF1R appears to mediate the effects of IGF2R on these neurons. Additionally, transcriptomic analysis of brain organoids derived from ASD patients indicated a significant association between IGF1R and ASD. Protein-protein interaction (PPI) and gene regulatory network (GRN) analyses further identified ASD susceptibility genes that interact with and regulate IGF1R expression. In conclusion, IGF1R emerges as a central node within the IGF signaling pathway, representing a potential common pathogenic mechanism and therapeutic target for ASD. These findings highlight the need for further investigation into the modulation of this pathway as a strategy for ASD intervention.
自闭症谱系障碍（ASD）是一种复杂的神经发育疾病，其特征为社交互动、沟通及重复行为存在缺陷。新出现的证据表明，胰岛素样生长因子（IGF）信号通路在ASD发病机制中起关键作用；然而，确切的致病机制仍不清楚。本研究采用多组学方法来探究IGF通路内ASD易感基因的致病机制。全外显子测序（WES）显示，在中国汉族ASD确诊患者队列以及SFARI SPARK WES数据库的ASD患者中，关键IGF信号成分，尤其是胰岛素样生长因子1受体（IGF1R）的罕见变异显著富集。随后，对ASD儿童皮质组织进行的单细胞RNA测序（scRNA-seq）表明，小白蛋白（PV）中间神经元中IGF受体的表达升高，提示对其发育有重大影响。值得注意的是，IGF1R似乎介导了IGF2R对这些神经元的作用。此外，对来自ASD患者的脑类器官进行的转录组分析表明，IGF1R与ASD之间存在显著关联。蛋白质-蛋白质相互作用（PPI）和基因调控网络（GRN）分析进一步确定了与IGF1R表达相互作用并调控其表达的ASD易感基因。总之，IGF1R成为IGF信号通路中的一个核心节点，代表了ASD潜在的共同致病机制和治疗靶点。这些发现凸显了进一步研究调节该通路作为ASD干预策略的必要性。
