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

Errichiello, Edoardo; Zagnoli-Vieira, Guido; Rizzi, Romana; Garavelli, Livia; Caldecott, Keith W.; Zuffardi, Orsetta

doi:10.1038/s10038-020-0800-4

Cited by 8 publications

(8 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, all individuals identified with TDP2 mutations exhibit a similar pathology of intellectual disability, seizures, and ataxia; a disease now denoted spinocerebellar ataxia autosomal recessive 23 (SCAR23) (Gómez-Herreros et al 2014 ; Zagnoli-Vieira et al 2018 ; Ciaccio et al 2019 ; Errichiello et al 2020 ; Zoghi et al 2021 ). Table 1 provides an overview of the patients reported to date with molecular and clinical details.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in TDP2 , encoding tyrosyl-DNA phosphodiesterase 2, have been associated with intellectual disability, cerebellar ataxia, and seizures; a disease known as autosomal recessive spinocerebellar ataxia, type 23 (SCAR23, OMIM #616949) (Gómez-Herreros et al 2014 ; Zagnoli-Vieira et al 2018 ; Ciaccio et al 2019 ; Errichiello et al 2020 ; Zoghi et al 2021 ). 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.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia

Zagnoli-Vieira

Bražina

Bogaert³

et al. 2023

Hum. Genet.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia

Zagnoli-Vieira

Bražina

Bogaert³

et al. 2023

Hum. Genet.

Self Cite

View full text Add to dashboard Cite

show abstract

“…These Top2 cleavage complexes (Top2ccs) are usually resolved immediately by Tyrosyl‐DNA Phosphodiesterase 2 (TDP2). Similar to TDP1, mutations in TDP2 result in a rare neurological disease termed spinocerebellar ataxia autosomal recessive 23 (SCAR23), further underscoring the potential toxicity of topoisomerase‐induced DNA damage in the nervous system (Zagnoli‐Vieira et al , 2018 ; Gómez‐Herreros et al , 2014 : 2; Errichiello et al , 2020 ).…”

Section: The Dna Damage Response (Ddr)mentioning

confidence: 99%

Mechanisms of DNA damage‐mediated neurotoxicity in neurodegenerative disease

Welch

Tsai

2022

EMBO Reports

View full text Add to dashboard Cite

Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan. While newer research has shown that DNA breaks and mutations may facilitate neuron diversity during development and neuronal function throughout life, a wealth of evidence indicates deficient DNA damage repair underlies many neurological disorders, especially age‐associated neurodegenerative diseases. Recently, efforts to clarify the molecular link between DNA damage and neurodegeneration have improved our understanding of how the genomic location of DNA damage and defunct repair proteins impact neuron health. Additionally, work establishing a role for senescence in the aging and diseased brain reveals DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.

show abstract

“…SCAR23 is an autosomal recessive syndrome that is characterized by treatment-resistant epilepsy, progressive ataxia, and cerebellar degeneration ( Gó Mez-Herreros et al, 2013 ; Gómez-Herreros et al, 2014 ). SCAR23 patients also display a later age of onset than other inherited ataxias, with symptom severity increasing during the second decade of life, suggesting SCAR23 is also a degenerative rather than developmental disorder ( Gómez-Herreros et al, 2014 ; Zagnoli-Vieira et al, 2018 ; Ciaccio et al, 2019 ; Errichiello et al, 2020 ). The underlying cause of SCAR23 are mutations within TDP2, and SCAR23 cells are deficient for the resolution of stalled TOP2ccs and are hypersensitive to ETP ( Gómez-Herreros et al, 2014 ).…”

Section: Topoisomerase-mediated Dna Damage and Neurological Diseasementioning

confidence: 99%

“…The underlying cause of SCAR23 are mutations within TDP2, and SCAR23 cells are deficient for the resolution of stalled TOP2ccs and are hypersensitive to ETP ( Gómez-Herreros et al, 2014 ). Several disease-causing mutations in TDP2 have been identified, each resulting in truncated mRNA expression and nonsense-mediated decay ( Gómez-Herreros et al, 2014 ; Zagnoli-Vieira et al, 2018 ; Ciaccio et al, 2019 ; Errichiello et al, 2020 ). Like SCAN1, mouse models of SCAR23 recapitulate the molecular and cellular phenotypes of human patients but do not display similar behavioral abnormalities such as ataxia or increased seizure propensity ( Gómez-Herreros et al, 2014 ).…”

Section: Topoisomerase-mediated Dna Damage and Neurological Diseasementioning

confidence: 99%

Topoisomerase-Mediated DNA Damage in Neurological Disorders

Crewe

Madabhushi

2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

The nervous system is vulnerable to genomic instability and mutations in DNA damage response factors lead to numerous developmental and progressive neurological disorders. Despite this, the sources and mechanisms of DNA damage that are most relevant to the development of neuronal dysfunction are poorly understood. The identification of primarily neurological abnormalities in patients with mutations in TDP1 and TDP2 suggest that topoisomerase-mediated DNA damage could be an important underlying source of neuronal dysfunction. Here we review the potential sources of topoisomerase-induced DNA damage in neurons, describe the cellular mechanisms that have evolved to repair such damage, and discuss the importance of these repair mechanisms for preventing neurological disorders.

show abstract

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

Cited by 8 publications

References 15 publications

Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia

Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia

Mechanisms of DNA damage‐mediated neurotoxicity in neurodegenerative disease

Topoisomerase-Mediated DNA Damage in Neurological Disorders

Contact Info

Product

Resources

About