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.