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Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23)

Journal of Human Genetics volume 65, pages 1135–1141 (2020)Cite this article

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Abstract

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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Data availability

The data that supports the findings of this study are available in the supplementary material of this article. Any other data will be made available on request from the corresponding author.

References

  1. Madabhushi R, Pan L, Tsai LH. DNA damage and its links to neurodegeneration. Neuron. 2014;83:266–82.

    Article  CAS  Google Scholar 

  2. Cortes Ledesma F, El Khamisy SF, Zuma MC, Osborn K, Caldecott KW. A human 5’-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature. 2009;461:674–8.

    Article  Google Scholar 

  3. Gómez-Herreros F, Romero-Granados R, Zeng Z, Alvarez-Quilón A, Quintero C, Ju L, et al. TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genet. 2013;9:e1003226.

    Article  Google Scholar 

  4. Gómez-Herreros F, Schuurs-Hoeijmakers JH, McCormack M, Greally MT, Rulten S, Romero-Granados R, et al. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat Genet. 2014;46:516–21.

    Article  Google Scholar 

  5. Kont YS, Dutta A, Mallisetty A, Mathew J, Minas T, Kraus C, et al. Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing. DNA Repair (Amst). 2016;43:38–47.

    Article  CAS  Google Scholar 

  6. Zagnoli-Vieira G, Bruni F, Thompson K, He L, Walker S, de Brouwer APM, et al. Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurol Genet. 2018;4:e262.

    Article  CAS  Google Scholar 

  7. Ciaccio C, Castello R, Esposito S, Pinelli M, Nigro V, Casari G, et al. Consolidating the role of TDP2 mutations in recessive spinocerebellar ataxia associated with pediatric onset drug resistant epilepsy and intellectual disability (SCAR23). Cerebellum. 2019;18:972–5.

    Article  Google Scholar 

  8. Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, et al. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet. 2002;32:267–72.

    Article  CAS  Google Scholar 

  9. Stoll G, Pietiläinen OPH, Linder B, Suvisaari J, Brosi C, Hennah W, et al. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat Neurosci. 2013;16:1228–37.

    Article  CAS  Google Scholar 

  10. King IF, Yandava CN, Mabb AM, Hsiao JS, Huang HS, Pearson BL, et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature. 2013;501:58–62.

    Article  CAS  Google Scholar 

  11. McKinnon PJ. Topoisomerases and the regulation of neural function. Nat Rev Neurosci. 2016;17:673–9.

    Article  CAS  Google Scholar 

  12. Holt R, Sykes NH, Conceição IC, Cazier JB, Anney RJ, Oliveira G, et al. CNVs leading to fusion transcripts in individuals with autism spectrum disorder. Eur J Hum Genet. 2012;20:1141–7.

    Article  CAS  Google Scholar 

  13. Thakurela S, Tiwari N, Schick S, Garding A, Ivanek R, Berninger B, et al. Mapping gene regulatory circuitry of Pax6 during neurogenesis. Cell Discov. 2016;2:15045.

    Article  CAS  Google Scholar 

  14. Smith AN, Miller LA, Radice G, Ashery-Padan R, Lang RA. Stage-dependent modes of Pax6-Sox2 epistasis regulate lens development and eye morphogenesis. Development. 2009;136:2977–85.

    Article  CAS  Google Scholar 

  15. Canela A, Maman Y, Huang SN, Wutz G, Tang W, Zagnoli-Vieira G, et al. Topoisomerase ii-induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity. Mol Cell. 2019;75:252–266.e8.

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Edoardo Errichiello & Orsetta Zuffardi

  2. Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK

    Guido Zagnoli-Vieira & Keith W. Caldecott

  3. Neurology Unit, Department of Neuro-Motor Diseases, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy

    Romana Rizzi

  4. Medical Genetics Unit, Department of Maternal and Child Health, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy

    Livia Garavelli

  5. Department of Genome Dynamics, Institute of Molecular Genetics of the ASCR, v.v.i, Prague, Czech Republic

    Keith W. Caldecott

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  1. Edoardo Errichiello
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  2. Guido Zagnoli-Vieira
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  3. Romana Rizzi
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  4. Livia Garavelli
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  5. Keith W. Caldecott
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  6. Orsetta Zuffardi
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Correspondence to Edoardo Errichiello.

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Errichiello, E., Zagnoli-Vieira, G., Rizzi, R. et al. Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23). J Hum Genet 65, 1135–1141 (2020). https://doi.org/10.1038/s10038-020-0800-4

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