Liu Chang, Wang Xin, Xu Chao, Liu Xiaoxiang, Ke Liyan, Li Ying, Zhang Hang, Tan Jianqiang, Tan Senwei, Zhang Zitong, Cheng Liang, Ren Yaqiong, Shi Lei
Department of Neurology, The First Traditional Chinese Medicine Hospital in Changde City, Changde, 415000, China.
National Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
BMC Neurol. 2025 Sep 1;25(1):370. doi: 10.1186/s12883-025-04378-z.
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.
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.
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.
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.
Not Applicable.
遗传性共济失调（HAs）是一类以进行性小脑变性为特征的神经退行性疾病，常染色体显性遗传性脊髓小脑共济失调（SCAs）是最常见的亚型。SCA3是全球最常见的形式，由ATXN3基因中的CAG重复序列扩增引起，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未完全明确。
我们采用综合多组学策略对一个五代中国遗传性共济失调家系进行研究。基因分析包括对血液来源的DNA进行靶向共济失调基因panel测序（TS）、全外显子测序（WES）和长读长全基因组测序（LR-WGS），以确定致病变异并确诊。转录组分析揭示了疾病相关的基因表达特征，随后进行功能注释和跨物种验证。为确保分析的严谨性，我们使用一个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流程。
基因分析确定了致病性ATXN3 - CAG重复序列扩增，其与受影响家庭成员的临床症状共分离。转录组分析显示，细胞外基质受体相互作用和粘着斑途径显著富集，同时存在与疾病进展相关的免疫失调和RNA剪接缺陷。跨物种分析发现了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。蛋白质-蛋白质相互作用网络强调AKT1是一个核心调节因子，以及其他关键节点（如TGFB1、MAPK3、CALM3、APP），而脑特异性分析突出了Mobp、Mal、Gja1和Klk6作为潜在的治疗靶点。
本研究使用LR-WGS在一个中国家系中对SCA3进行了基因确诊，克服了短读长测序的诊断局限性。综合分析揭示了保守的SCA3进展特征以及潜在的生物标志物，可用于未来的非侵入性监测。从机制上讲，本研究确定细胞外基质受体相互作用/粘着斑、免疫反应和RNA剪接失调是关键的致病因素。这些发现提供了可操作的治疗靶点，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，对重复序列扩增疾病具有更广泛的意义。
不适用。
