2. Academic Validation
  3. SCGN deficiency is a risk factor for autism spectrum disorder

SCGN deficiency is a risk factor for autism spectrum disorder

  • Signal Transduct Target Ther. 2023 Jan 2;8(1):3. doi: 10.1038/s41392-022-01225-2.
Zhe Liu # 1,  Shuai Tan # 2,  Lianyu Zhou # 3,  Li Chen 1,  Mingfeng Liu 1,  Wang Wang 2,  Yingying Tang 1,  Qin Yang 1,  Sensen Chi 2,  Peiyan Jiang 3,  Yue Zhang 4 5,  Yonghua Cui 6,  Junhong Qin 1,  Xiao Hu 1,  Shenglong Li 2,  Qi Liu 7,  Lu Chen 1,  Song Li 3,  Ezra Burstein 7,  Wei Li 8 9,  Xiaohu Zhang 10,  Xianming Mo 11,  Da Jia 12
Affiliations

Affiliations

  • 1 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, 610041, Chengdu, China.
  • 2 Department of Immunology, College of Basic Medicine, Chongqing Medical University, 400010, Chongqing, China.
  • 3 Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China.
  • 4 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, 100045, Beijing, China.
  • 5 MOE Key Laboratory of Major Diseases in Chidren, Beijing Children's Hospital, Capital Medical University, 100045, Beijing, China.
  • 6 Department of Psychology, Beijing Children's Hospitl, Capital Medical University, 100045, Beijing, China.
  • 7 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 8 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, 100045, Beijing, China. liwei@bch.com.cn.
  • 9 MOE Key Laboratory of Major Diseases in Chidren, Beijing Children's Hospital, Capital Medical University, 100045, Beijing, China. liwei@bch.com.cn.
  • 10 Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China. zhangxh_alex@163.com.
  • 11 Department of Pediatric Surgery and Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China. xmingmo@scu.edu.cn.
  • 12 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, 610041, Chengdu, China. JiaDa@scu.edu.cn.
  • # Contributed equally.
PMID: 36588101 DOI: 10.1038/s41392-022-01225-2
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.

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