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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).
J Hum Genet. 2020 Jul 10 [Online ahead of print]JH

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.

Authors+Show Affiliations

Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy. edoardo.errichiello@unipv.it.Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK.Neurology Unit, Department of Neuro-Motor Diseases, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy.Medical Genetics Unit, Department of Maternal and Child Health, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy.Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK. Department of Genome Dynamics, Institute of Molecular Genetics of the ASCR, v.v.i, Prague, Czech Republic.Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32651480

Citation

Errichiello, Edoardo, et al. "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, 2020.
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. 2020.
Errichiello, E., Zagnoli-Vieira, G., Rizzi, R., Garavelli, L., Caldecott, K. W., & Zuffardi, O. (2020). 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. https://doi.org/10.1038/s10038-020-0800-4
Errichiello E, 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. 2020 Jul 10; PubMed PMID: 32651480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23). AU - Errichiello,Edoardo, AU - Zagnoli-Vieira,Guido, AU - Rizzi,Romana, AU - Garavelli,Livia, AU - Caldecott,Keith W, AU - Zuffardi,Orsetta, Y1 - 2020/07/10/ PY - 2020/04/24/received PY - 2020/06/29/accepted PY - 2020/7/12/entrez JF - Journal of human genetics JO - J. Hum. Genet. N2 - 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. SN - 1435-232X UR - https://www.unboundmedicine.com/medline/citation/32651480/Characterization_of_a_novel_loss-of-function_variant_in_TDP2_in_two_adult_patients_with_spinocerebellar_ataxia_autosomal_recessive_23_(SCAR23) L2 - https://antibodies.cancer.gov/detail/CPTC-TDP2-1 DB - PRIME DP - Unbound Medicine ER -
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