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
{"title":"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。","authors":"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","doi":"10.1136/jmg-2023-109385","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>We identified a novel candidate gene <i>NASP</i> (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 t<i>NASP</i>(Q289X) subjects the expression of t<i>NASP</i> to nonsense-mediated decay. t<i>NASP</i> 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 t<i>NASP</i>, t<i>NASP</i>(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 t<i>NASP</i> mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in <i>Caenorhabditis elegans</i>. Two additional patients with ASD were found carrying deletion or deleterious mutation in the <i>NASP</i> gene.</p><p><strong>Conclusion: </strong>We identified novel epigenetic mechanisms mediated by t<i>NASP</i> which may contribute to the pathogenesis of ASD and its immune comorbidity.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<i>NASP</i> gene contributes to autism by epigenetic dysregulation of neural and immune pathways.\",\"authors\":\"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\",\"doi\":\"10.1136/jmg-2023-109385\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>We identified a novel candidate gene <i>NASP</i> (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 t<i>NASP</i>(Q289X) subjects the expression of t<i>NASP</i> to nonsense-mediated decay. t<i>NASP</i> 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 t<i>NASP</i>, t<i>NASP</i>(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 t<i>NASP</i> mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in <i>Caenorhabditis elegans</i>. Two additional patients with ASD were found carrying deletion or deleterious mutation in the <i>NASP</i> gene.</p><p><strong>Conclusion: </strong>We identified novel epigenetic mechanisms mediated by t<i>NASP</i> which may contribute to the pathogenesis of ASD and its immune comorbidity.</p>\",\"PeriodicalId\":16237,\"journal\":{\"name\":\"Journal of Medical Genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-06-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jmg-2023-109385\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2023-109385","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
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.
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.