孤独症AUTS2基因罕见变异筛选及其对鼠神经元树突发育的影响  

Screening rare variations of AUTS2 in children with autism and its effect on dendritic development of neurons of rat

作　　者：王晗 林芬 王琳彦 张天 汪子琪 卢天兰[1] 贾美香[1] 李俊[1] 刘靖[1] 王力芳[1] WANG Han;LIN Fen;WANG Linyan;ZHANG Tian;WANG Ziqi;LU Tianlan;JIA Meixiang;LI Jun;LIU Jing;WANG Lifang(Peking University Six th Hospital,Peking University Institute of Mental Health,NHC Key Laboratory of Mental Halth(Peking University),National Clinical Research Centerfor Mental Disorders(Peking University Sixth Hospital),Bejing 100083,China)

机构地区：[1]北京大学第六医院,北京大学精神卫生研究所,国家卫生健康委员会精神卫生学重点实验室(北京大学),国家精神心.理疾病临床医学研究中心(北京大学第六医院),北京100083

出　　处：《中国心理卫生杂志》2021年第4期338-343,共6页Chinese Mental Health Journal

基　　金：国家重点研发计划(2017YFC1309901);广东省重点领域研发计划(2019B030335001);国家自然科学基金(81671363);国家自然科学基金(81971283)。

摘　　要：目的:探讨中国汉族孤独症患者是否携带孤独症易感候选基因2(AUTS2)有害罕见变异,及其对鼠神经元树突发育的影响。方法:对96例符合DSM-IV孤独症诊断标准的中国汉族孤独症患者AUTS2基因进行靶向测序筛选罕见变异,进一步扩大样本在766例孤独症患者和864例正常对照中采用Sanger测序法进行验证,继而构建有害罕见变异质粒,转染至敲低内源性Auts2的原代培养SD乳鼠皮层神经元,观察神经元树突总长度和分支数量。结果:AUTS2基因2个罕见错义突变c.44G>T(Arg15Leu)和c.1774C>G(Pro592Ala)仅孤独症患者携带,功能预测为有害突变。此2个罕见错义突变导致SD乳鼠皮层神经元顶树突和基树突的总长度和分支数量均显著减少(P<0.05)。结论:中国汉族人群孤独症AUTS2基因存在2个有害罕见错义突变,能影响大鼠神经元树突发育,可能参与孤独症的发病。Objective:To screen the pathogenic rare variants of the autism susceptibility candidate 2(AUTS2) in patients with autism of Han Chinese descent, and explore its effects on the development of neuronal dendrites of rat.Methods:Targeted sequencing of transcription regulation region and whole exons of AUTS2 in 96 Han Chinese patients with autism was performed for screening rare variants.All children met the autism diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth edition(DSM-IV).Then the rare variants were validated by Sanger sequencing in a further expanded sample of 766 autistic patients and 864 healthy controls.Plasmids containing deleterious rare variants were constructed and transfected into Auts2-knocked down cortical neurons of SD neonatal rat in vitro.The total length and number of branches of the neuronal dendrites were observed.Results:This study detected that two patients with autism carried rare missense mutations in AUTS2,c.44 G> T(Arg15 Leu) and c.1774 C> G(Pro592 Ala),respectively.Functional prediction suggested that these two rare variants were deleterious and might affect the function of AUTS2.However, these variants were not found in the healthy controls.The total dendritic length and number of branches of cortical neurons transfected plasmids containing these two rare variants of the AUTS2 were significantly reduced, respectively(P<0.05).Conclusion:There are two deleterious rare missense mutations in AUTS2 detected in autistic children of Han Chinese, which could affect the development of neuron dendrites in rats and may be involved in the pathogenesis of autism.

关 键 词：孤独症 AUTS2基因 罕见变异 神经元 树突发育 

分 类 号：R749.94[医药卫生—神经病学与精神病学]