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Published on: March 15, 2013
Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers
Chang Liu1, Xin Wang2,3, Chao Xu2,4
1Department of Neurology, The First Traditional Chinese Medicine Hospital in Changde City, Changde, 415000, China.
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.
