ArticleAnnals of neurology2016
DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases.
Article in Annals of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
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131 citing papers in PubMed, 227 citations in OpenAlex.
- Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism.PNAS nexus · 2026Article
- Tandem repeats in human brain evolution and disease susceptibility.Molecules and cells · 2026Review
- Double strand breaks drive toxicity in a Huntington's disease mouse model with or without somatic expansion.Nature communications · 2026Article
- Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.Brain : a journal of neurology · 2026Article
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
- Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1.Biomedicines · 2025Review
- Decoding Huntington's disease: a global survey on symptoms and genetic testing practices.European archives of psychiatry and clinical neuroscience · 2025Article
- DNA extrusion size determines pathway choice during CAG repeat expansion.Nucleic acids research · 2025Article
- Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1.Nature communications · 2025Article
- Huntington's chorea: emerging fields in therapeutics (Review).Neurogenetics · 2025Review
- Emerging drivers of DNA repeat expansions.Biochemical Society transactions · 2025Review
- Interventionally targeting somatic CAG expansions can be a rapid disease-modifying therapeutic avenue: Preclinical evidence.bioRxiv : the preprint server for biology · 2025Article
- Article
- Msh2-Msh3 DNA-binding is not sufficient to promote trinucleotide repeat expansions in Saccharomyces cerevisiae.Genetics · 2025Article
- Tissue-Specific Effects of the DNA Helicase FANCJ/BRIP1/BACH1 on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders.International journal of molecular sciences · 2025Article
- Review
- Genomic characterization of Huntington's disease genetic modifiers informs drug target tractability.Brain communications · 2025Article
- Advances in chromosomal microarray analysis: Transforming neurology and neurosurgery.Brain & spine · 2025Review
- Decoding Nucleotide Repeat Expansion Diseases: Novel Insights fromInternational journal of molecular sciences · 2024Review
- Structural and Dynamical Properties of Nucleic Acid Hairpins Implicated in Trinucleotide Repeat Expansion Diseases.Biomolecules · 2024Review
71 more citing papers are in PubMed but not listed here.
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25 authors at 11 institutions in 7 countries.
Funding
Abstract
objectiveThe 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.
methodsWe 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.
resultsIn 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.
interpretationWe 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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