ArticleNature neuroscience2022
Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset.
Article in Nature neuroscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 82 citations in OpenAlex.
- Clinical implications of loss of interruption variants for diagnosis, genetic counselling, and clinical trials in Huntington's disease.Journal of Huntington's disease · 2026Review
- TRACE: Open-source software for quantifying somatic variation of tandem repeats by capillary electrophoresis.Journal of Huntington's disease · 2026Article
- Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.Nature communications · 2026Article
- Somatic CRISPR editing ofbioRxiv : the preprint server for biology · 2026Article
- Induced pluripotent stem cells from a transgenic minipig model of Huntington's disease reveal early metabolic changes.Disease models & mechanisms · 2026Article
- Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways.Life science alliance · 2026Article
- Double strand breaks drive toxicity in a Huntington's disease mouse model with or without somatic expansion.Nature communications · 2026Article
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- USP7 deubiquitinase stabilizes FAN1 to support DNA crosslink repair and suppress CAG repeat expansion.Nature communications · 2026Article
- TRACE: Open-Source Software for Quantifying Somatic Variation of Tandem Repeats by Capillary Electrophoresis.bioRxiv : the preprint server for biology · 2026Article
- Sequence Variants in Small CAG Repeat Expansions of theNeurology · 2026Article
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
- Huntingtin in the amygdaloid basolateral complex is correlated with Vonsattel staging in Huntington's disease.Brain communications · 2026Article
- Disruption of protein-protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency.NAR cancer · 2025Article
- Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1.Nature communications · 2025Article
- Living with Risk, Aging with Uncertainty: A Narrative Review of Health and Genetic Vulnerability in Huntington's Disease.Biomedicines · 2025Review
- BA9 Transcriptomics in Huntington's Disease 80-Gene Signature and MIR219A2-Linked Targets.International journal of molecular sciences · 2025Article
- Emerging drivers of DNA repeat expansions.Biochemical Society transactions · 2025Review
- Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects.Nature genetics · 2025Article
Corrections and comments
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Authors and funding
34 authors at 8 institutions in 3 countries.
Funding
Abstract
The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.