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Confirming TDP2 Mutation in Spinocerebellar Ataxia Autosomal Recessive 23 (SCAR23) Guido Zagnoli-Vieira, Francesco Bruni, Kyle Thompson, Et Al

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Confirming TDP2 Mutation in Spinocerebellar Ataxia Autosomal Recessive 23 (SCAR23) Guido Zagnoli-Vieira, Francesco Bruni, Kyle Thompson, Et Al ARTICLE OPEN ACCESS Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23) Guido Zagnoli-Vieira, BSc, Francesco Bruni, PhD,* Kyle Thompson, PhD, Langping He, MD, PhD, Correspondence Sarah Walker, PhD, Arjan P.M. de Brouwer, PhD, Robert Taylor, PhD, FRCPath, Dmitriy Niyazov, MD, Dr. Caldecott [email protected] and Keith W. Caldecott, PhD Neurol Genet 2018;4:e262. doi:10.1212/NXG.0000000000000262 Abstract 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, bio- chemistry, and subcellular mitochondrial analyses for this study. Results We have identified a patient in the United States with SCAR23 harboring the same homozy- gous 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. *Current address: Department of Biosciences Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy. From the Genome Damage and Stability Centre (G.Z-V., K.W.C.), University of Sussex, Falmer, Brighton, United Kingdom; Wellcome Centre for Mitochondrial Research (F.B., K.T., L.H., R.T.), Institute of Neuroscience, Newcastle University, Tyne, United Kingdom; Sussex Drug Discovery Centre (S.W.), University of Sussex, Falmer, Brighton, United Kingdom; Department of Human Genetics (A.P.M.d.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; and Medical Genetics (A.P.M.d.B., D.N.), Ochsner Health Center for Children, New Orleans, LA. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary 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. DNA is under constant threat from attack by endogenous and also easily fatigued and a 14-year-old maternal half-sister exogenous electrophilic molecules,1 and DNA topoisomerase with attention deficit hyperactivity disorder (ADHD). enzymes can introduce DNA breaks as abortive intermediates – of their activity.2 4 Topoisomerase “poisons” such as etopo- The patient has difficulty keeping balance and has an ataxic side inhibit the ligation activity of topoisomerase 2 (TOP2), gait. He has been tested several times for abnormalities in thereby promoting the formation of abortive DNA double- blood, urine, and CSF, and by MRI and EEG, and only the strand break (DSB) intermediates that require DSB repair. latter is abnormal. Seizures began at the age of 5 months, and DSBs are repaired in cells by either homologous his EEGs show increased slowing and occasional spikes in the recombination–mediated repair or by nonhomologous end right posterior quadrant, and during drowsiness, he had 2 joining (NHEJ).2 The repair of TOP2-induced DSBs by generalized bursts of polyspike and slow-wave activity at NHEJ involves the enzyme tyrosyl DNA phosphodiesterase 2 a frequency of 4–5 Hz. The patient’s 180K oligoarray, very (TDP2), which removes trapped topoisomerase peptide from long chain fatty acids, carbohydrate-deficient transferrin, CSF the 59-termini at the DSB and thereby allows the DNA ends to lactate, and neurotransmitters and plasma amino acids were – be ligated.3 5 The loss of TDP2 in mouse results in reduced normal. expression of >100 genes in the brain,6 and TDP2 mutation in humans has been associated with intellectual disability, seiz- The patient exhibited several phenotypes consistent with mi- ures, and ataxia,6 a disease now denoted as spinocerebellar tochondrial dysfunction such as hypotonia, low energy, fati- ataxia, autosomal recessive 23 (SCAR23). To date, our un- gability, hypersomnia, failure to thrive, short stature, derstanding of SCAR23 has been limited by the availability of constipation, neutropenia, hyponatremia, cardiac arrhythmia, only 3 Irish siblings with a mutation in TDP2 and by the lack and gastrointestinal dysmotility. Consistent with this, electron of availability of fibroblast cell lines from these patients for transport chain (ETC) studies on muscle biopsy at age 1 year molecular and cellular characterization. Here, we have showed a severe reduction of complex I + III and II + III addressed these limitations and identified an SCAR23 patient activity, which satisfied the major Walker criteria after cor- in the United States with the same homozygous TDP2 mu- rection for increased citrate synthase activity. CoQ10 de- tation as present in the Irish siblings, confirming the associ- ficiency was suggested based on the complex I + III and II + III ation of this disease with mutated TDP2. In addition, we have deficiency, and his metabolic tests were abnormal with the characterized at the molecular and cellular level primary pa- high lactate and high lactate/pyruvate ratio. The patient was tient fibroblasts from the current SCAR23 patient. placed on ubiquinol, carnitine, and leucovorin, and anecdot- ally, he responded well (particularly to liposomal ubiquinol, the active or reduced form of CoQ10) in terms of energy and Methods developmental progress. He is reportedly no longer sleepy and lethargic and has a stable gait, but is “still behind” in language Patient case report and cognitive skills and is in special education. He still has The patient is currently a 6-year-old caucasian boy from idiopathic fevers but has not been admitted to the hospital for the United States presenting with developmental delay, 15 months. He does not have as many infections but still has microcephaly, and failure to thrive. His mother and father gastric dysmotility. His seizures have reduced in frequency. are aged 29 years and 32 years, respectively, and there is no previous family history of related disease, but there is Standard protocol approvals, registrations, and possible consanguinity (3rd cousins). The patient started patient consents walking at the age of 14 months and talking at 3 years, his We confirm that we have received approval from an in- hearing was reportedly normal, but he did not have audi- stitutional ethics standards committee for this work, and we tory brainstem response. The patient is easily fatigued, and have written informed consent for research from the guardian his parents reported that he eats excessively, becomes ir- of the patient for participation in this study. ritable, and falls asleep sometimes for days or up to 2 weeks. He is now below the fifth percentile for weight and Exome sequencing and haplotype analysis 5% for height, with a body mass index at <5%. He has Whole-exome sequencing (WES) (trio study) of the patient was a G-tube and is followed by a dietitian and receives nutri- performed by GeneDx using the Agilent Clinical Research tional liquid supplements (PediaSure; Abbott, Lake Forest, Exome kit to target the exonic regions and flanking splice IL). He has a history of constipation and is followed up by junctions of the genome. These targeted regions were sequenced a gastroenterologist. He has a 12-year-old brother who is simultaneously by massively parallel (NextGen, Irvine, CA) 2 Neurology: Genetics | Volume 4, Number 4 | August 2018 Neurology.org/NG sequencing on an Illumina HiSeq sequencing system with 37°C. TDP2-mutated patient primary human fibroblasts were 100bp paired-end reads. Bidirectional sequence was assembled, established from a patient’s skin biopsy and were denoted 850- aligned to reference gene sequences based on human genome BR. The control human fibroblast cell line 1-BR.3 (denoted build GRCh37/UCSC hg19, and analyzed for sequence var- here for simplicity as 1-BR) was previously derived from an iants in the selected genes or regions of interest using a custom- unrelated normal individual and has been described pre- developed analysis tool (Xome Analyzer). Capillary sequencing viously.8 For complementation experiments, we used 1-BR was used to confirm all potentially pathogenic variants identi- cells that were immortalized previously with hTERT (denoted fied in this individual. Sequence alterations were reported as 1-BR hTERT) and a derivative of 850-BR immortalized in according to the nomenclature guidelines of the Human the current study by retroviral-mediated hTERT expression Genome Variation Society. The WES identified a homozygous and selected in a medium containing 1 μg/ml puromycin splice site mutation (c.425+1G>A) in the TDP2 gene. For (denoted as 850-BR hTERT). For complementation with comparison of the current patient with the Irish pedigree human TDP2, 850-BR hTERT cells were transfected with ei- previously reported,6 we conducted haplotype analysis.
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