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Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)

Lookup NU author(s): Dr Francesco Bruni, Dr Kyle Thompson, Dr Langping He, Dr Arjan De Brouwer, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 American Academy of Neurology. Objective To address the relationship between mutations in the DNA strand break repair protein tyrosyl DNA phosphodiesterase 2 (TDP2) and spinocerebellar ataxia autosomal recessive 23 (SCAR23) and to characterize the cellular phenotype of primary fibroblasts from this disease. Methods We have used exome sequencing, Sanger sequencing, gene editing and cell biology, biochemistry, and subcellular mitochondrial analyses for this study. Results We have identified a patient in the United States with SCAR23 harboring the same homozygous TDP2 mutation as previously reported in 3 Irish siblings (c.425+1G>A). The current and Irish patients share the same disease haplotype, but the current patient lacks a homozygous variant present in the Irish siblings in the closely linked gene ZNF193, eliminating this as a contributor to the disease. The current patient also displays symptoms consistent with mitochondrial dysfunction, although levels of mitochondrial function in patient primary skin fibroblasts are normal. However, we demonstrate an inability in patient primary fibroblasts to rapidly repair topoisomerase-induced DNA double-strand breaks (DSBs) in the nucleus and profound hypersensitivity to this type of DNA damage. Conclusions These data confirm the TDP2 mutation as causative for SCAR23 and highlight the link between defects in nuclear DNA DSB repair, developmental delay, epilepsy, and ataxia.

Publication metadata

Author(s): Zagnoli-Vieira G, Bruni F, Thompson K, He L, Walker S, de Brouwer APM, Taylor R, Niyazov D, Caldecott KW

Publication type: Article

Publication status: Published

Journal: Neurology: Genetics

Year: 2018

Volume: 4

Issue: 4

Online publication date: 01/08/2018

Acceptance date: 24/05/2018

Date deposited: 12/02/2019

ISSN (electronic): 2376-7839

Publisher: Lippincott Williams and Wilkins


DOI: 10.1212/NXG.0000000000000262


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