PT  - JOURNAL ARTICLE
AU  - Zagnoli-Vieira, Guido
AU  - Bruni, Francesco
AU  - Thompson, Kyle
AU  - He, Langping
AU  - Walker, Sarah
AU  - de Brouwer, Arjan P.M.
AU  - Taylor, Robert
AU  - Niyazov, Dmitriy
AU  - Caldecott, Keith W.
TI  - Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)
AID  - 10.1212/NXG.0000000000000262
DP  - 2018 Aug 01
TA  - Neurology Genetics
PG  - e262
VI  - 4
IP  - 4
4099  - http://ng.neurology.org/content/4/4/e262.short
4100  - http://ng.neurology.org/content/4/4/e262.full
SO  - Neurol Genet2018 Aug 01; 4
AB  - Objective 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.DSB=double-strand break; ETC=electron transport chain; FCS=fetal calf serum; NHEJ=nonhomologous end joining; SCAR23=spinocerebellar ataxia, autosomal recessive 23; TDP2=tyrosyl DNA phosphodiesterase 2; WCE=whole-cell extract; WES=Whole-exome sequencing