ArticlePLoS genetics2013
Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 174 papers.
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Who cites it
174 citing papers in PubMed, 251 citations in OpenAlex.
- Redundant mispair excision mechanisms in eukaryotic DNA mismatch repair.Nucleus (Austin, Tex.) · 2026Review
- The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease.Brain : a journal of neurology · 2026Article
- Targeted quantification assays for DNA repair and handling proteins and interactions in Huntington's disease models.bioRxiv : the preprint server for biology · 2026Article
- Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.Nature communications · 2026Article
- Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism.PNAS nexus · 2026Article
- Somatic CRISPR editing ofbioRxiv : the preprint server for biology · 2026Article
- Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways.Life science alliance · 2026Article
- Mechanism of MutLβ-dependent DNA expansions.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion.NAR molecular medicine · 2026Article
- ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Review
- Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Single-nucleus transcriptomics of an engineered pig model reveals microglia-T cell interactions driving Huntington's disease neurodegeneration.Nature biomedical engineering · 2026Article
- Mismatch repair MLH complexes make distinct contributions to post-replicative mismatch repair versus trinucleotide repeat expansions.bioRxiv : the preprint server for biology · 2026Article
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
- Silmitasertib, an FDA-designated orphan CK2 inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- A shared DNA-repeat toxicity threshold, reached somatically at cell-type-specific rates, unites cortical and striatal neurodegeneration in Huntington's disease.bioRxiv : the preprint server for biology · 2025Article
- Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?Molecular neurobiology · 2025Review
- DNA extrusion size determines pathway choice during CAG repeat expansion.Nucleic acids research · 2025Article
- Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding.Nature communications · 2025Article
- Review
114 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 7 institutions in 2 countries.
Funding
Abstract
The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.
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