长读测序鉴定了ATXN3重复扩增,转录组学揭示了脊髓小脑性共济失调3型的疾病进展生物标志物和药物靶点。

IF 2.2 3区 医学 Q3 CLINICAL NEUROLOGY
Chang Liu, Xin Wang, Chao Xu, Xiaoxiang Liu, Liyan Ke, Ying Li, Hang Zhang, Jianqiang Tan, Senwei Tan, Zitong Zhang, Liang Cheng, Yaqiong Ren, Lei Shi
{"title":"长读测序鉴定了ATXN3重复扩增,转录组学揭示了脊髓小脑性共济失调3型的疾病进展生物标志物和药物靶点。","authors":"Chang Liu, Xin Wang, Chao Xu, Xiaoxiang Liu, Liyan Ke, Ying Li, Hang Zhang, Jianqiang Tan, Senwei Tan, Zitong Zhang, Liang Cheng, Yaqiong Ren, Lei Shi","doi":"10.1186/s12883-025-04378-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Hereditary ataxias (HAs) are neurodegenerative disorders characterized by progressive cerebellar degeneration, with autosomal dominant spinocerebellar ataxias (SCAs) representing the most prevalent subtype. SCA3, the most common form worldwide, is caused by CAG repeat expansions in ATXN3, resulting in pathogenic ataxin-3 aggregation. However, the underlying molecular mechanisms driving disease progression remain incompletely understood.</p><p><strong>Methods: </strong>We utilized an integrated multi-omics strategy to investigate a five-generation Chinese HA pedigree. Genetic analyses included targeted ataxia panel sequencing (TS), whole-exome sequencing (WES), and long-read whole-genome sequencing (LR-WGS) of blood-derived DNA to identify causal variants and confirm diagnosis. Transcriptomic profiling revealed disease-associated gene expression signatures, followed by functional annotation and cross-species validation. To ensure analytical rigor, we further validated our bioinformatic pipeline using an independent ulcerative colitis (UC) dataset.</p><p><strong>Results: </strong>Genetic analysis identified pathogenic ATXN3-CAG repeat expansions that co-segregated with clinical symptoms in affected family members. Transcriptomic profiling showed significant enrichment in ECM-receptor interaction and focal adhesion pathways, along with immune dysregulation and RNA splicing defects associated with disease progression. Cross-species analysis discovered conserved blood biomarkers (C3/ALS2/SLC35A2↓ and THBS1/CAMTA1↑), strongly correlated with clinical progression. Protein-protein interaction network emphasized AKT1 as a central regulator, along with other key hubs (e.g., TGFB1, MAPK3, CALM3, APP), while brain-specific analyses highlighted Mobp, Mal, Gja1 and Klk6 as potential therapeutic targets.</p><p><strong>Conclusions: </strong>This study genetically confirms SCA3 in a Chinese pedigree using LR-WGS, overcoming the diagnostic limitations of short-read sequencing. Comprehensive analyses revealed conserved SCA3 progression signatures with potential biomarkers for future non-invasive monitoring. Mechanistically, this study identified dysregulation in ECM-receptor interaction/focal adhesion, immune response, and RNA splicing as key pathogenic contributors. These findings provide both actionable therapeutic targets and demonstrate the clinical utility of integrated multi-omics approaches for SCA3 diagnosis and patient stratification, with broader implications for repeat expansion disorders.</p><p><strong>Trial registration: </strong>Not Applicable.</p>","PeriodicalId":9170,"journal":{"name":"BMC Neurology","volume":"25 1","pages":"370"},"PeriodicalIF":2.2000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403609/pdf/","citationCount":"0","resultStr":"{\"title\":\"Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers and druggable targets for spinocerebellar ataxia type 3.\",\"authors\":\"Chang Liu, Xin Wang, Chao Xu, Xiaoxiang Liu, Liyan Ke, Ying Li, Hang Zhang, Jianqiang Tan, Senwei Tan, Zitong Zhang, Liang Cheng, Yaqiong Ren, Lei Shi\",\"doi\":\"10.1186/s12883-025-04378-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Hereditary ataxias (HAs) are neurodegenerative disorders characterized by progressive cerebellar degeneration, with autosomal dominant spinocerebellar ataxias (SCAs) representing the most prevalent subtype. SCA3, the most common form worldwide, is caused by CAG repeat expansions in ATXN3, resulting in pathogenic ataxin-3 aggregation. However, the underlying molecular mechanisms driving disease progression remain incompletely understood.</p><p><strong>Methods: </strong>We utilized an integrated multi-omics strategy to investigate a five-generation Chinese HA pedigree. Genetic analyses included targeted ataxia panel sequencing (TS), whole-exome sequencing (WES), and long-read whole-genome sequencing (LR-WGS) of blood-derived DNA to identify causal variants and confirm diagnosis. Transcriptomic profiling revealed disease-associated gene expression signatures, followed by functional annotation and cross-species validation. To ensure analytical rigor, we further validated our bioinformatic pipeline using an independent ulcerative colitis (UC) dataset.</p><p><strong>Results: </strong>Genetic analysis identified pathogenic ATXN3-CAG repeat expansions that co-segregated with clinical symptoms in affected family members. Transcriptomic profiling showed significant enrichment in ECM-receptor interaction and focal adhesion pathways, along with immune dysregulation and RNA splicing defects associated with disease progression. Cross-species analysis discovered conserved blood biomarkers (C3/ALS2/SLC35A2↓ and THBS1/CAMTA1↑), strongly correlated with clinical progression. Protein-protein interaction network emphasized AKT1 as a central regulator, along with other key hubs (e.g., TGFB1, MAPK3, CALM3, APP), while brain-specific analyses highlighted Mobp, Mal, Gja1 and Klk6 as potential therapeutic targets.</p><p><strong>Conclusions: </strong>This study genetically confirms SCA3 in a Chinese pedigree using LR-WGS, overcoming the diagnostic limitations of short-read sequencing. Comprehensive analyses revealed conserved SCA3 progression signatures with potential biomarkers for future non-invasive monitoring. Mechanistically, this study identified dysregulation in ECM-receptor interaction/focal adhesion, immune response, and RNA splicing as key pathogenic contributors. These findings provide both actionable therapeutic targets and demonstrate the clinical utility of integrated multi-omics approaches for SCA3 diagnosis and patient stratification, with broader implications for repeat expansion disorders.</p><p><strong>Trial registration: </strong>Not Applicable.</p>\",\"PeriodicalId\":9170,\"journal\":{\"name\":\"BMC Neurology\",\"volume\":\"25 1\",\"pages\":\"370\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403609/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BMC Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12883-025-04378-z\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMC Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12883-025-04378-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:遗传性共济失调(HAs)是一种以进行性小脑变性为特征的神经退行性疾病,常染色体显性脊柱小脑共济失调(SCAs)是最常见的亚型。SCA3是世界上最常见的形式,是由ATXN3的CAG重复扩增引起的,导致致病性ataxin-3聚集。然而,驱动疾病进展的潜在分子机制仍然不完全清楚。方法:我们利用综合多组学策略研究了一个五代中国HA家系。遗传分析包括靶向共济失调小组测序(TS)、全外显子组测序(WES)和血液来源DNA的长读全基因组测序(LR-WGS),以确定因果变异并确认诊断。转录组学分析揭示了疾病相关的基因表达特征,随后进行了功能注释和跨物种验证。为了确保分析的严谨性,我们使用独立的溃疡性结肠炎(UC)数据集进一步验证了我们的生物信息学管道。结果:遗传分析鉴定出致病ATXN3-CAG重复扩增,该扩增与患病家庭成员的临床症状共分离。转录组学分析显示,与疾病进展相关的ecm受体相互作用和局灶黏附途径以及免疫失调和RNA剪接缺陷显著富集。跨物种分析发现保守的血液生物标志物(C3/ALS2/SLC35A2↓和THBS1/CAMTA1↑)与临床进展密切相关。蛋白-蛋白相互作用网络强调AKT1是一个中心调节因子,以及其他关键枢纽(如TGFB1、MAPK3、CALM3、APP),而脑特异性分析强调了Mobp、Mal、Gja1和Klk6是潜在的治疗靶点。结论:本研究利用LR-WGS从遗传学上证实了一个中国家系的SCA3,克服了短读测序的诊断局限性。综合分析显示,保守的SCA3进展特征具有潜在的生物标志物,可用于未来的无创监测。在机制上,本研究确定了ecm受体相互作用/局灶黏附、免疫反应和RNA剪接的失调是主要的致病因素。这些发现提供了可行的治疗靶点,并证明了综合多组学方法在SCA3诊断和患者分层中的临床应用,对重复扩张疾病具有更广泛的意义。试验注册:不适用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers and druggable targets for spinocerebellar ataxia type 3.

Background: Hereditary ataxias (HAs) are neurodegenerative disorders characterized by progressive cerebellar degeneration, with autosomal dominant spinocerebellar ataxias (SCAs) representing the most prevalent subtype. SCA3, the most common form worldwide, is caused by CAG repeat expansions in ATXN3, resulting in pathogenic ataxin-3 aggregation. However, the underlying molecular mechanisms driving disease progression remain incompletely understood.

Methods: We utilized an integrated multi-omics strategy to investigate a five-generation Chinese HA pedigree. Genetic analyses included targeted ataxia panel sequencing (TS), whole-exome sequencing (WES), and long-read whole-genome sequencing (LR-WGS) of blood-derived DNA to identify causal variants and confirm diagnosis. Transcriptomic profiling revealed disease-associated gene expression signatures, followed by functional annotation and cross-species validation. To ensure analytical rigor, we further validated our bioinformatic pipeline using an independent ulcerative colitis (UC) dataset.

Results: Genetic analysis identified pathogenic ATXN3-CAG repeat expansions that co-segregated with clinical symptoms in affected family members. Transcriptomic profiling showed significant enrichment in ECM-receptor interaction and focal adhesion pathways, along with immune dysregulation and RNA splicing defects associated with disease progression. Cross-species analysis discovered conserved blood biomarkers (C3/ALS2/SLC35A2↓ and THBS1/CAMTA1↑), strongly correlated with clinical progression. Protein-protein interaction network emphasized AKT1 as a central regulator, along with other key hubs (e.g., TGFB1, MAPK3, CALM3, APP), while brain-specific analyses highlighted Mobp, Mal, Gja1 and Klk6 as potential therapeutic targets.

Conclusions: This study genetically confirms SCA3 in a Chinese pedigree using LR-WGS, overcoming the diagnostic limitations of short-read sequencing. Comprehensive analyses revealed conserved SCA3 progression signatures with potential biomarkers for future non-invasive monitoring. Mechanistically, this study identified dysregulation in ECM-receptor interaction/focal adhesion, immune response, and RNA splicing as key pathogenic contributors. These findings provide both actionable therapeutic targets and demonstrate the clinical utility of integrated multi-omics approaches for SCA3 diagnosis and patient stratification, with broader implications for repeat expansion disorders.

Trial registration: Not Applicable.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
BMC Neurology
BMC Neurology 医学-临床神经学
CiteScore
4.20
自引率
0.00%
发文量
428
审稿时长
3-8 weeks
期刊介绍: BMC Neurology is an open access, peer-reviewed journal that considers articles on all aspects of the prevention, diagnosis and management of neurological disorders, as well as related molecular genetics, pathophysiology, and epidemiology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信