NASP 基因通过对神经和免疫途径的表观遗传失调导致自闭症。

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-06-20 DOI:10.1136/jmg-2023-109385
Sipeng Zhang, Jie Yang, Dandan Ji, Xinyi Meng, Chonggui Zhu, Gang Zheng, Joseph Glessner, Hui-Qi Qu, Yuechen Cui, Yichuan Liu, Wei Wang, Xiumei Li, Hao Zhang, Zhanjie Xiu, Yan Sun, Ling Sun, Jie Li, Hakon Hakonarson, Jin Li, Qianghua Xia
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引用次数: 0

摘要

背景:表观遗传学对自闭症谱系障碍(ASD)的病因学有重大贡献,可能蕴藏着预防ASD发展的独特机会。我们的目的是找出与自闭症谱系障碍病因学有关的新型表观遗传学基因:方法:我们对 ASD 家庭进行了基于三重全外显子组测序。采用基因组编辑技术在相关细胞系中敲除候选致病基因。对候选基因进行ATAC-seq、ChIP-seq和RNA-seq分析,以研究基因敲除(KO)或突变对其功能的影响:结果:我们在一个中国核心家庭中发现了一个新的候选基因NASP(核自身抗原精子蛋白),该基因可导致自闭症表观遗传失调。tNASP KO增加了染色质的可及性,促进了富含突触信号的基因启动子的活跃状态,并导致神经信号和免疫信号通路中的基因表达上调。与野生型 tNASP 相比,tNASP(Q289X) 提高了脑内富集表达基因的染色质可及性。RNA-seq显示,参与神经和免疫信号传导的基因受到了tNASP突变的影响,这与秀丽隐杆线虫中nasp-1突变的表型影响和分子效应是一致的。我们还发现另外两名 ASD 患者携带 NASP 基因缺失或有害突变:我们发现了由 tNASP 介导的新型表观遗传学机制,这种机制可能有助于 ASD 及其免疫合并症的发病机制。
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NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

Background: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology.

Methods: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene.

Results: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene.

Conclusion: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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