DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases
Open accessAbstract
Objective: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods: We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results: In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10 –5 ). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs ( p = 1.52 × 10 –5 ) and all SCAs ( p = 2.22 × 10 –4 ) and rs1805323 in PMS2 with HD+SCAs ( p = 3.14 × 10 –5 ), all in the same direction as in the HD GWAS. Interpretation: We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990
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CAG expansion in HD is dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2.
“Notably, CAG expansion has been found to be dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2, whose detection of oxidized or mismatched bases in these repetitive elements could potentially elicit erroneous repair, leading to CAG expansion (Kovtun et al, 2007; Bettencourt et al, 2016; Pinto et al, 2013; Manley et al, 1999; Lee et al, 2017, 1).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Bettencourt et al, 2016
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- Authors
- Bettencourt, C., Hensman‐Moss, D., Flower, M., Wiethoff, S., Brice, A., Goizet, C., Stevanin, G., Koutsis, G., Karadima, G., Panas, M., Yescas‐Gómez, P., García‐Velázquez, L. E., Alonso‐Vilatela, M. E., Lima, M., Raposo, M., Traynor, B., Sweeney, M., Wood, N., Giunti, P., The SPATAX Network, Durr, A., Holmans, P., Houlden, H., Tabrizi, S. J., & Jones, L.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- Department of Neurodegenerative Disease, Institute of Neurology University College London London WC1N 3BG United Kingdom
- UCL Queen Square Institute of Neurology (GB)
- Hertie Institute for Clinical Brain Research (DE)
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm U 1127, CNRS UMR 7225, Sorbonne Universités UPMC University Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM) Paris France
- National and Kapodistrian University of Athens (GR)
- Neurogenetics Unit, 1st Department of Neurology University of Athens Medical School, Eginition Hospital 115 28 Athens Greece
- Neurogenetics Department, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez” Mexico City CP14269 Mexico
- Instituto Nacional de Neurología y Neurocirugía (MX)
- Universidade dos Açores (PT)
- National Institutes of Health (US)
- University College London Hospitals NHS Foundation Trust (GB)
- Cardiff University (GB)
- Corresponding author
- Jones, Lesley
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2016-05-06
- Volume
- 79
- Issue
- 6
- Pages
- 983-990
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4914895
- OpenAlex
- W2342089554
- Cited by
- 227
- References
- 41
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 24 · 2023: 14 · 2022: 26 · 2021: 36 · 2020: 33 · 2019: 23 · 2018: 30 · 2017: 12 · 2016: 3
- FWCI
- 12.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Annals of Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- HAL (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (FP7/2007–2013, MR/L010305/1, WT093205 MA, 305121, WT104033/Z/14/Z)
- Multiple System Atrophy Trust (WT093205MA)
- National Institute for Health and Care Research (WT093205MA, ACF-2009-18-016, FP7/2007–2013, NF-SI-0515-10082)
- Brain Research Trust
- University College London (WT093205MA)
- European Commission (2007–2013, FP7 2007-2013, FP7/2007, 305121)
- University College London Hospitals NHS Foundation Trust
- Medical Research Council (MR/L02053X/1, FP7/20072013, MR/P007015/1, MR/L012936/1, MR/J003832/1, MR/L010305/1, MC_PC_14108, MR/J004758/1, WT093205 MA)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- polyglutamine diseases, Huntington's disease, spinocerebellar ataxia, DNA repair genes, age of onset, genetic modifiers, CAG repeat expansion, somatic repeat expansion, FAN1, PMS2, single nucleotide polymorphisms, neurodegenerative diseases
- MeSH terms
- Mismatch Repair Endonuclease PMS2, DNA Repair, Endodeoxyribonucleases, Exodeoxyribonucleases, Humans, Huntington Disease, Mutation, Age of Onset, Trinucleotide Repeat Expansion, Polymorphism, Single Nucleotide, Spinocerebellar Ataxias, Genome-Wide Association Study, Multifunctional Enzymes
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