Evidence map›Paper›PMID 40890629›Full record

ArticleBMC neurology2025

Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers and druggable targets for spinocerebellar ataxia type 3.

Chang Liu, Xin Wang, Chao Xu, Xiaoxiang Liu, Liyan Ke, Ying Li, Hang Zhang, Jianqiang Tan, Senwei Tan, Zitong Zhang and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in BMC neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Chang Liu *Department of Neurology, The First Traditional Chinese Medicine Hospital in Changde City, Changde, 415000, China.
Xin Wang *National Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Chao Xu *National Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Xiaoxiang LiuDepartment of Radiology, The First People's Hospital of Changde City, Changde, 415000, China.
Liyan KeNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Ying LiNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Hang ZhangNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Jianqiang TanDepartment of Genetics and Endocrinology, Liuzhou Maternity and Child Health Care Hospital, Liuzhou, 545001, China.
Senwei TanNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Zitong ZhangNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China.
Liang ChengNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China. liangcheng@hrbmu.edu.cn.
Yaqiong RenMcKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100005, China. ryq327@163.com.
Lei ShiNational Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150081, China. shilei_0328@hrbmu.edu.cn.

Funding

National Key Research and Development Program of China 2020YFA0804000National Natural Science Foundation of China 62222104
6 · The paper itself

Abstract

backgroundHereditary 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.

methodsWe 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.

resultsGenetic 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.

conclusionsThis 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 registrationNot Applicable.

Indexed as

Ataxin-3Machado-Joseph DiseaseTranscriptomeTrinucleotide Repeat ExpansionAdultBiomarkersDisease ProgressionExome SequencingFemaleGene Expression ProfilingHumansMaleMiddle AgedPedigreeRepressor ProteinsWhole Genome SequencingAtaxin-3ATXN3 protein, humanBiomarkersRepressor ProteinsATXN3BiomarkerLong-read Whole-genome SequencingMachado-Joseph DiseaseMJDRepeat ExpansionSCA3Spinocerebellar Ataxia Type 3

Identifiers

PMID40890629
PMCPMC12403609

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.