SCGN deficiency is a risk factor for autism spectrum disorder

Zhe Liu, Shuai Tan, Lianyu Zhou, Li Chen, Mingfeng Liu, Wang Wang, Yingying Tang, Qin Yang, Sensen Chi, Peiyan Jiang, Yue Zhang, Yonghua Cui, Junhong Qin, Xiao Hu, Shenglong Li, Qi Liu, Lu Chen, Song Li, Ezra Burstein, Wei LiXiaohu Zhang, Xianming Mo, Da Jia

Research output: Contribution to journalArticlepeer-review

Abstract

Autism spectrum disorder (ASD) affects 1–2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.

Original languageEnglish (US)
Article number3
JournalSignal Transduction and Targeted Therapy
Volume8
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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