KEYWORDS
TDP2 , topoisomerase II (TOP2), double-strand breaks (DSBs),
spinocerebellar ataxia, intellectual disability, epilepsy, speech delay,
whole-exome sequencing (WES)
The impairment of DNA repair systems and accumulation of DNA double
strand breaks (DSBs) are involved in the pathogenesis of different
neurodegenerative diseases, such as Alzheimer’s disease and amyotrophic
lateral sclerosis (Madabhushi et al., 2014). TDP2 (6p22.3)
encodes the enzyme tyrosyl-DNA phosphodiesterase 2 that is required for
efficient repair of topoisomerase II (TOP2)-induced DSBs by
non-homologous end-joining (NHEJ) (Cortes Ledesma et al., 2009;
Gómez-Herreros et al., 2013). In addition, TDP2 has been shown to
be involved in neural development and maintenance by regulating
brain-specific gene transcripts (Gómez-Herreros et al., 2014), and it is
expressed throughout the brain of adult mice, especially in the dentate
gyrus of the hippocampus and in the dopaminergic substantia nigraneurons, where it exerts a proapoptotic function by interacting with
Parkinson’s disease-associated DJ-1/PARK7 mutant proteins (Zucchelli et
al., 2009).
Biallelic inactivating variants of TDP2 have been identified in
five individuals with intellectual disability, seizures and ataxia,
defining a new nosological entity known as spinocerebellar ataxia
autosomal recessive 23 (SCAR23; OMIM #616949) (Gómez-Herreros et al.,
2014; Zagnoli-Vieira et al., 2018; Ciaccio et al., 2019). TOP2-induced
DSBs have been implicated in genome instability and oncogenic chromosome
translocation (Gómez-Herreros et al., 2017). On the other hand, the use
of “TOP2 poisons” ̵̶ such as etoposide and doxorubicin ̵̶ has been
suggested in clinical practice as adjuvant therapy to sensitize cancer
cells toward TOP2 poisons (Kont et al., 2016).
We characterized a novel TDP2 variant in two adult siblings (aged
45 and 39 years), supporting the causative role of TDP2loss-of-function variants in SCAR23 and further delineating the related
clinical phenotype. We also addressed the open question of whetherTDP2 may be involved in susceptibility to other neurological
conditions as well as cancer.