RNA Foci in Two bi-Allelic RFC1 Expansion Carriers
Taishi Wada1, Hiroshi Doi1, Masaki Okubo1
1Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Annals of Neurology
|December 8, 2023
Summary
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is linked to RFC1 gene repeat expansions. Pathological analysis revealed RNA foci, suggesting RNA toxicity contributes to this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a rare, late-onset, autosomal recessive neurodegenerative disorder.
- It is caused by repeat expansions in the RFC1 gene, specifically biallelic AAGGG/ACAGG repeat expansions (AAGGG-exp/ACAGG-exp).
- Recent findings suggest RFC1 loss-of-function may also contribute to CANVAS pathogenesis.
Purpose of the Study:
- To investigate the pathological changes in patients with CANVAS.
- To explore the role of RNA toxicity in the pathogenesis of CANVAS.
Main Methods:
- Autopsy of 2 patients with CANVAS harboring biallelic ACAGG-exp and AAGGG-exp.
- RNA fluorescence in situ hybridization (FISH) on neuronal nuclei from affected tissues.
Main Results:
- RNA FISH revealed the presence of CCTGT- and CCCTT-containing RNA foci in the neuronal nuclei of both patients.
- These RNA foci were observed in tissues exhibiting neuronal loss.
Conclusions:
- The findings suggest that RNA toxicity, potentially mediated by these RNA foci, may play a significant role in the pathogenesis of CANVAS.
- Further research into RNA-mediated mechanisms is warranted for understanding and potentially treating CANVAS.
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