Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy
Open accessAbstract
Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy letter Mutations in genes involved in singlestrand break repair (SSBR) have been linked to hereditary cerebellar ataxias.Notably, Ataxia-oculomotor apraxia 1 (AOA1 (MIM: 2 08 920)), Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1 (MIM: 6 07 250)) and Ataxia-oculomotor apraxia 4 (AOA4 (MIM: 616267616267616267)) are associated with mutations in APTX (MIM: 606350), TDP1 (MIM: 607198) and PNKP (MIM: 605610), respectively.1 Recently, compound heterozygous mutations in XRCC1 were identified in one individual with ocular motor apraxia, cerebellar ataxia and axonal neuropathy. 2 However, as this study only identified a single case, the causal role of XRCC1 in Autosomal Recessive Cerebellar Ataxia (ARCA) remained in question and required replication in additional cases.Here we recapitulate and broaden this phenotype in two patients of Pakistani decent who were not known to be related.This confirms the role of XRCC1 in cerebellar ataxia.
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The majority of DNA damage disorders typically present in early childhood, with the exception of AOA5.
“With the exception of AOA5, which seems to have manifested exclusively in adults so far (Hoch et al, 2017: 1; O’Connor et al, 2018: 1), the majority of DNA damage disorders typically present in early childhood.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as O’Connor et al, 2018: 1
Mutations in XRCC1 cause Ataxia with Oculomotor apraxia Type 5 (AOA5).
“Defective XRCC1 manifests in individuals as Ataxia with Oculomotor apraxia Type 5 (AOA5), another slow‐progressing neurodegenerative disease.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as O’Connor et al, 2018: 1
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Cites
Single-strand break repair and genetic disease
Caldecott, K. W. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2380 · Cited by 1,034 · see citing works
XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
Care4Rare Canada Consortium, Hoch, N. C., Hanzlikova, H., Rulten, S. L., Tétreault, M., Komulainen, E., Ju, L., Hornyak, P., Zeng, Z., Gittens, W., et al. (2017) · Nature · doi:10.1038/nature20790 · Cited by 269 · see citing works
The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1
Lee, Y., Katyal, S., Li, Y., El‐Khamisy, S. F., Russell, H. R., Caldecott, K. W., & McKinnon, P. J. (2009) · Nature Neuroscience · doi:10.1038/nn.2375 · Cited by 114 · see citing works
Ahmed, E. A., Rijbroek, A. D. B.-V., Kal, H. B., et al. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.108.071662 · Cited by 112 · see citing works
Oxidation state of the XRCC1 N-terminal domain regulates DNA polymerase β binding affinity
Cuneo, M. J., & London, R. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914077107 · Cited by 74 · see citing works
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Neuronal enhancers are hotspots for DNA single-strand break repair
Wu, W., Kargbo-Hill, S. E., Nathan, W. J., Paiano, J., Callen, E., Wang, D., Shinoda, K., van Wietmarschen, N., Colón-Mercado, J. M., Zong, D., et al. (2021) · Nature · doi:10.1038/s41586-021-03468-5 · Cited by 223 · see citing works
Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
Welch, G., & Tsai, L. (2022) · The EMBO Reports · doi:10.15252/embr.202154217 · Cited by 129 · see citing works
- Authors
- O’Connor, E., Vandrovcova, J., Bugiardini, E., Chelban, V., Manole, A., Davagnanam, I., Wiethoff, S., Pittman, A., Lynch, D. S., Efthymiou, S., Marino, S., Manzur, A. Y., Roberts, M., Hanna, M. G., Houlden, H., Matthews, E., & Wood, N. W.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- Queen Mary University of London (GB)
- Great Ormond Street Hospital (GB)
- Salford Royal NHS Foundation Trust (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- O’Connor, Emer
- ORCID
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2018-02-22
- Volume
- 89
- Issue
- 11
- Pages
- 1230-1232
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC6227798
- OpenAlex
- W2788043212
- Cited by
- 29
- References
- 5
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 4
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Wellcome Trust (104033)
- Brain Research UK
- National Institute for Health and Care Research (NF-SI-0507-10376, NF-SI-0515-10082, NF-SI-0513-10064)
- Parkinson's UK (G-1107)
- Ataxia UK
- Brain Research Trust
- European Commission (305121)
- Rosetrees Trust
- University College London Hospitals NHS Foundation Trust
- Medical Research Council (MR/K000608/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- XRCC1, cerebellar ataxia, peripheral neuropathy, autosomal recessive cerebellar ataxia, single-strand break repair, compound heterozygosity, hereditary ataxia, Pakistani patients
- MeSH terms
- X-ray Repair Cross Complementing Protein 1, Adult, Cerebellar Ataxia, DNA Mutational Analysis, Humans, Male, Mutation, Pedigree, Peripheral Nervous System Diseases, Young Adult
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