SCGN deficiency is a risk factor for autism spectrum disorder

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

作者地址："[Liu, Zhe; Chen, Li; Liu, Mingfeng; Tang, Yingying; Yang, Qin; Qin, Junhong; Hu, Xiao; Chen, Lu; Jia, Da] Sichuan Univ, West China Second Univ Hosp, State Key Lab Biotherapy & Collaborat Innovat Ctr, Dept Paediat, Chengdu 610041, Peoples R China; [Tan, Shuai; Wang, Wang; Chi, Sensen; Li, Shenglong] Chongqing Med Univ, Coll Basic Med, Dept Immunol, Chongqing 400010, Peoples R China; [Zhou, Lianyu; Jiang, Peiyan; Li, Song] Army Med Univ, Xinqiao Hosp, Dept Neurosurg, Chongqing, Peoples R China; [Zhang, Yue; Li, Wei] Beijing Pediat Res Inst, Beijing Key Lab Genet Birth Defects, Beijing 100045, Peoples R China; [Zhang, Yue; Li, Wei] Capital Med Univ, Beijing Childrens Hosp, MOE, Key Lab Major Dis Chidren, Beijing 100045, Peoples R China; [Cui, Yonghua] Capital Med Univ, Beijing Childrens Hosp, Dept Psychol, Beijing 100045, Peoples R China; [Liu, Qi; Burstein, Ezra] Univ Texas Southwestern Med Ctr, Dept Internal Med, Dallas, TX 75390 USA; [Zhang, Xiaohu] Sichuan Univ, West China Univ Hosp 2, Chinese Univ Hong Kong Joint Lab Reprod Med, Chengdu, Peoples R China; [Mo, Xianming] Sichuan Univ, West China Hosp, Dept Pediat Surg & Lab Stem Cell Biol, Chengdu 610041, Peoples R China"

通信作者："Jia, D (通讯作者)，Sichuan Univ, West China Second Univ Hosp, State Key Lab Biotherapy & Collaborat Innovat Ctr, Dept Paediat, Chengdu 610041, Peoples R China.; Li, W (通讯作者)，Beijing Pediat Res Inst, Beijing Key Lab Genet Birth Defects, Beijing 100045, Peoples R China.; Li, W (通讯作者)，Capital Med Univ, Beijing Childrens Hosp, MOE, Key Lab Major Dis Chidren, Beijing 100045, Peoples R China.; Zhang, XH (通讯作者)，Sichuan Univ, West China Univ Hosp 2, Chinese Univ Hong Kong Joint Lab Reprod Med, Chengdu, Peoples R China.; Mo, XM (通讯作者)，Sichuan Univ, West China Hosp, Dept Pediat Surg & Lab Stem Cell Biol, Chengdu 610041, Peoples R China."

来源：SIGNAL TRANSDUCTION AND TARGETED THERAPY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000906376700003

JCR分区：Q1

影响因子：40.8

年份：2023

卷号：8

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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."

基金机构："National Key Research and Development Program of China [2022YFA1100056, 2018YFC1005004]; Natural Science Foundation of China (NSFC) [92254302, 31871429]; National Science Fund for Distinguished Young Scholars [32125012]; 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYGD20007, ZYJC18011]; Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN20210436]"

基金资助正文："We thank Drs. Wentong Meng and Qiaorong Huang (Laboratory of Stem Cell Biology, West China Hospital, Sichuan University) for assistance with experimental technology. Research in the authors' laboratory is supported by National Key Research and Development Program of China (2022YFA1100056, 2018YFC1005004), Natural Science Foundation of China (NSFC) grants (#92254302, #31871429), National Science Fund for Distinguished Young Scholars (#32125012), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD20007 and ZYJC18011 to X.M.), and Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN20210436)."