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Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)
journal contribution
posted on 2023-06-09, 14:24 authored by Guido Zagnol-iVieira, Francesco Bruni, Kyle Thompson, Langping He, Sarah Walker, Arjan P M de Brouwer, Robert Taylor, Dimitriy Niyazov, Keith CaldecottKeith CaldecottObjective 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.
Funding
Cellular and Pathological Responses to Chromosomal DNA Single-Strand Breaks; G2053; MRC-MEDICAL RESEARCH COUNCIL; MR/P010121/1
Genome Damage and Stability Centre - studentships; G1673; MRC-MEDICAL RESEARCH COUNCIL; MR/N50189X/1
SIDSCA: Defective DNA Damage Responses in Dominant Neurodegenerative Diseases; G1930; EUROPEAN UNION; 694996
Non-homologous End-Joining Protein Complexes and Genome Stability; G1305; CANCER RESEARCH UK; C6563/A16771
History
Publication status
- Published
File Version
- Published version
Journal
Neurology GeneticsISSN
2376-7839Publisher
Wolters Kluwer Health, Inc.External DOI
Issue
4Volume
4Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-08First Open Access (FOA) Date
2018-08-08First Compliant Deposit (FCD) Date
2018-08-08Usage metrics
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