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Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia
Guido Zagnoli-Vieira1,2, Jan Brazina3, Kris Van Den Bogaert4
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9RQ, UK. guido.zagnoli@outlook.com.
Abstract:
Mutations in TDP2, encoding tyrosyl-DNA phosphodiesterase 2, have been associated with a syndromal form of autosomal recessive spinocerebellar ataxia, type 23 (SCAR23). This is a very rare and progressive neurodegenerative disorder described in only nine patients to date, and caused by splice site or nonsense mutations that result in greatly reduced or absent TDP2 protein. TDP2 is required for the rapid repair of DNA double-strand breaks induced by abortive DNA topoisomerase II (TOP2) activity, important for genetic stability in post-mitotic cells such as neurons. Here, we describe a sibship that is homozygous for the first TDP2 missense mutation (p.Glu152Lys) and which presents with clinical features overlapping both SCAR23 and Fanconi anemia (FA). We show that in contrast to previously reported SCAR23 patients, fibroblasts derived from the current patient retain significant levels of TDP2 protein. However, this protein is catalytically inactive, resulting in reduced rates of repair of TOP2-induced DNA double-strand breaks and cellular hypersensitivity to the TOP2 poison, etoposide. The TDP2-mutated patient-derived fibroblasts do not display increased chromosome breakage following treatment with DNA crosslinking agents, but both TDP2-mutated and FA cells exhibit increased chromosome breakage in response to etoposide. This suggests that the FA pathway is required in response to TOP2-induced DNA lesions, providing a possible explanation for the clinical overlap between FA and the current TDP2-mutated patients. When reviewing the relatively small number of patients with SCAR23 that have been reported, it is clear that the phenotype of such patients can extend beyond neurological features, indicating that the TDP2 protein influences not only neural homeostasis but also other tissues as well.
Insights
A novel missense mutation in TDP2 causes a spinocerebellar ataxia with features overlapping Fanconi anemia. This inactive TDP2 protein impairs DNA repair, highlighting TDP2
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- Mutations in TDP2 (tyrosyl-DNA phosphodiesterase 2) are linked to spinocerebellar ataxia type 23 (SCAR23), a rare neurodegenerative disorder.
- TDP2 is crucial for repairing DNA double-strand breaks from topoisomerase II (TOP2) activity, maintaining genetic stability in neurons.
- Previous SCAR23 cases involved loss-of-function mutations, leading to absent or significantly reduced TDP2 protein.
Purpose of the Study:
- To investigate the impact of a novel TDP2 missense mutation on protein function and cellular phenotype.
- To explore the clinical overlap between SCAR23 and Fanconi anemia (FA) in patients with this mutation.
- To elucidate the role of the FA pathway in response to TOP2-induced DNA damage.
Main Methods:
- Genetic sequencing to identify mutations in TDP2.
- Fibroblast cell culture from patients and controls.
- Assays to measure TDP2 protein levels and catalytic activity.
- DNA double-strand break repair rate assessment.
- Cellular sensitivity testing to TOP2 poisons (etoposide) and DNA crosslinking agents.
- Chromosome breakage analysis.
Main Results:
- A sibship was identified with the first reported homozygous missense mutation in TDP2 (p.Glu152Lys).
- Patient-derived fibroblasts retained TDP2 protein, but it was catalytically inactive, impairing DNA repair.
- Cells showed hypersensitivity to etoposide, a TOP2 poison, with increased chromosome breakage.
- Unlike typical FA cells, these fibroblasts did not show increased breakage with DNA crosslinking agents.
- Both TDP2-mutated and FA cells exhibited increased chromosome breakage upon etoposide treatment.
Conclusions:
- The TDP2 p.Glu152Lys missense mutation results in catalytically inactive TDP2, causing a SCAR23 phenotype with FA overlap.
- The Fanconi anemia pathway is implicated in repairing TOP2-induced DNA lesions, explaining the clinical overlap.
- TDP2's function extends beyond neural homeostasis, influencing other tissues and potentially contributing to broader clinical phenotypes.
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