SCGN deficiency is a risk factor for autism spectrum disorder

We identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk factor 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. Mechanistically, Scgn deficiency leads to reduced oxytocin signaling and inflammatory activation in animal models as well as ASD probands. Importantly, we demonstrate that 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.

本研究鉴定出突触传递（synaptic transmission）调节因子分泌粒蛋白（secretagogin, SCGN），并证实其为孤独症谱系障碍（Autism Spectrum Disorder, ASD）的新型风险因子。研究在ASD先证者中检出SCGN的两种杂合功能丧失突变；在斑马鱼与小鼠中敲除Scgn基因，可诱发类孤独症行为。机制研究显示，在动物模型与ASD先证者体内，Scgn缺陷均可导致催产素信号通路减弱与炎症活化。尤为重要的是，本研究证实，给予催产素与抗炎药物可缓解SCGN缺陷引发的ASD相关异常表型。综上，本研究明确了潜在孤独症遗传风险因子SCGN与催产素能信号通路（oxytocinergic signaling）及免疫应答的病理失调之间的交汇关联，为携带SCGN缺陷的ASD患者提供了潜在治疗策略。