Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23)
Open accessAbstract
TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.
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Mutations in TDP2 result in spinocerebellar ataxia autosomal recessive 23 (SCAR23).
“mutations in TDP2 result in a rare neurological disease termed spinocerebellar ataxia autosomal recessive 23 (SCAR23)”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Errichiello et al, 2020
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References 25 · Cited by 12
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- Authors
- Errichiello, E., Zagnoli-Vieira, G., Rizzi, R., Garavelli, L., Caldecott, K. W., & Zuffardi, O.
- Affiliations
- University of Pavia (IT)
- University of Sussex (GB)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Corresponding author
- Errichiello, Edoardo
- ORCID
- Venue
- Journal of Human Genetics
- Published
- 2020-07-10
- Volume
- 65
- Issue
- 12
- Pages
- 1135-1141
- ISSN
- 1434-5161 (ISSN-L)
- 1435-232X
- OpenAlex
- W3041627605
- Cited by
- 12
- References
- 25
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK (16771)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- TDP2, loss-of-function mutations, splice site mutation, exon skipping, nonsense-mediated mRNA decay, topoisomerase II, intellectual disability, refractory seizures, clinical phenotype, adult-onset ataxia
- MeSH terms
- Loss of Function Mutation, Adult, DNA-Binding Proteins, Female, Genes, Recessive, Humans, Male, Intellectual Disability, Middle Aged, Phosphoric Diester Hydrolases, Spinocerebellar Ataxias
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