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Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches
Open accessAbstract
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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“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 Pinto et al, 2013
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BackgroundTherapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases
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“Another event was recovered in MLH3, which plays a role in the DNA mismatch repair pathway (MMR) and is connected to Huntington’s disease and the somatic expansion of CAG repeats [45,46].”
BackgroundCAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs
Anderson, R., Das, M. R., Chang, Y., Farenhem, K. L., Schmitz, C. O., & Jain, A. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.01.006 · Cited by 8
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“In addition to functional MSH2, at least four other components of the DNA mismatch repair pathway are necessary to mediate high levels of CAG•CTG somatic expansion (Manley et al., 1999; van Den Broek et al., 2002; Gomes-Pereira et al., 2004; Foiry et al., 2006; Seriola et al., 2011; Pinto et al., 2013; Tomé et al., 20…”
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“On the other hand, multiple MMR proteins (including MSH2, MSH3, MLH1, and MLH3) have been shown to be required for somatic expansions of CAG repeats in mice (Manley et al. 1999; López Castel et al. 2010; Pinto et al. 2013).”
Emerging drivers of DNA repeat expansions
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“A caveat, however, is that instability driven by MMR proteins is usually relatively small in scale, such that only a few repetitive units are added per human cell division or mouse generation [48,51,59,60].”
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Belgrad, J., Summers, A., Landles, C., Greene, J. R., Hildebrand, S. R., Knox, E. G., Sapp, E., Yamada, N., Furgal, R. C., Miller, R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.24.661398 · Cited by 7
“Somatic expansion is facilitated by the mismatch repair (MMR) pathway 12,19,20 .”
Bhattarai, M., Juhari, W. K. W., Lama, R., Pun, C. B., Yusof, W., Rahman, W. F. W. A., Zakaria, A. D., Noordin, K. B. A. A., Shrestha, T. R., & Zilfalil, B. A. (2020) · Medical Journal of Indonesia · doi:10.13181/mji.oa.203633 · Cited by 6
“60–69 10 (23) 8 (23) 2 (25) 9 (24) 1 (20)”
Harder, A. (2022) · Child s Nervous System · doi:10.1007/s00381-021-05436-w · Cited by 5
Kansal, R., Li, X., Shen, J. J., Samuel, D., Laningham, F. H., Lee, H., Panigrahi, G. B., Shuen, A. Y., Kantarci, S., Dorrani, N., et al. (2015) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22319 · Cited by 6
“Both reactions are also known to require MutLalpha (Panigrahi et al., 2012), where the trinucleotide instability has been suggested to also require Mlh1-Mlh3 (MutLgamma) in mice (Pinto et al., 2013).”
BackgroundSelf-citationTell‐Martí, G., Puig‐Butillé, J. A., Giménez‐Xavier, P., Segu-Roig, A., Potrony, M., Bádenas, C., Álvarez, V., Millán, J. M., Trujillo-Tiebas, M. J., Ramos‐Arroyo, M. A., et al. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0305-5 · Cited by 6
Zhang, D., Huo, J., Li, R., Zhang, Y., Wang, Z., & Li, X. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27662 · Cited by 6
“MLH1 is involved in several cellular processes independent of mismatch repair.(43) The intracellular Ca dysregulation caused by mutant ATP2C1 encoded SPCA1 results in an altered extracellular microenvironment and cell‐matrix contact as well as intracellular changes, such as the expansion of Golgi.”
BackgroundSomatic CAG Repeat Stability in a Transgenic Sheep Model of Huntington’s Disease
Handley, R. R., Reid, S. J., Burch, Z. N., Jacobsen, J. C., Gillis, T., Correia, K., Rudiger, S. R., McLaughlin, C. J., Bawden, C. S., MacDonald, M. E., et al. (2024) · Journal of Huntington s Disease · doi:10.3233/jhd-231516 · Cited by 5
Self-citationAretz, J., Jeyasankar, G., Salerno-Kochan, A., Thomsen, M., Thieulin-Pardo, G., Haque, T., Monteagudo, E., Felsenfeld, D. P., Finley, M., Vogt, T. F., et al. (2024) · bioRxiv · doi:10.1038/s41467-025-59324-x · Cited by 6
Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing
Yang, B., Borgeaud, A. C., Buřičová, M., Aeschbach, L., Rodríguez‐Lima, O., Buendía, G. A. R., Cinesi, C., Taylor, A. S., Baubec, T., & Dion, V. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab255 · Cited by 5
“The case of HDAC5 is possibly more complex as its partner, HDAC3, has been shown to play a role in the deacetylation of MSH3 (30), a known modifier of repeat instability (14,47,50,52–54).”
Butzke, D., Dulisch, N., Dunst, S., Steinfath, M., Neves, M., Mathiak, B., & Grune, B. (2020) · doi:10.21203/rs.3.rs-16454/v1 · Cited by 5
“Reference abstracts PMID 19735549 (DCIS, ductal carcinoma in situ (22)) and 24204323 (Huntington’s disease (19)) were chosen because of a priori knowledge of available in vitro methodology (i.”
Cheng, Y., Nocula-Lugowska, G., Ramirez, J. A., Fan, X., Jin, F., Jiang, Z., Bennett, E. M., Li, J., Hokanson, D. E., Grandhi, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.24.568451 · Cited by 5
Jimenez, D. A., Miller, C. J., Walker, A. K., Anupindi, K., Hayward, B. E., Lorenzi, H. A., Usdin, K., & Zhao, X.-N. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.13.607839 · Cited by 5
“Then, when levels of PMS2 are systematically increased in a Pms2 -/- cell line, expansion rates rise, peaking at expansion rates similar to those seen in WT cells for both repeats.”
DNA extrusion size determines pathway choice during CAG repeat expansion
Bhatia, M., Phadte, A. S., Lakhina, A., Carlo, A. R. M., Barndt, S., & Pluciennik, A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1393 · Cited by 4
Azevedo, A., Kovalenko, M. V., Andrew, M. A., Zhang, F., Lee, J., Wheeler, V. C., & Pinto, M. R. (2017) · Porto Biomedical Journal · doi:10.1016/j.pbj.2017.07.083 · Cited by 4
Self-citationIntersecting impact of CAG repeat and huntingtin knockout in stem cell-derived cortical neurons
Stocksdale, J. T., Leventhal, M. J., Lam, S., Xu, Y., Wang, Y., Wang, K. Q., Thomas, R., Faghihmonzavi, Z., Raghav, Y., Smith-Geater, C., et al. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106914 · Cited by 6
“…around a dominant gain of aberrant function, and in identifying genetic modifiers of disease onset, which to date are largely functionally related to DNA mismatch repair (Goold et al., 2019; Genetic Modifiers of Huntington ’ s Disease, C, 2015; Ferguson and Tabrizi, 2023; Pinto et al., 2013).”
A small molecule kicks repeat expansion into reverse
Flower, M. D., & Tabrizi, S. J. (2020) · Nature Genetics · doi:10.1038/s41588-020-0577-6 · Cited by 4
Mystery of Expansion: DNA Metabolism and Unstable Repeats
Grishchenko, I. V., Purvinsh, Y. V., & Yudkin, D. V. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-41283-8_7 · Cited by 5
The instability of the Huntington's disease CAG repeat mutation
Wheeler, V. C., Stone, J. C., Massey, T. H., & Pinto, R. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95672-7.00003-0 · Cited by 4
Self-citationChoi, D. E., Shin, J. W., Zeng, S., Hong, E. P., Jang, J.-H., Loupe, J. M., Wheeler, V. C., Stutzman, H. E., Kleinstiver, B. P., & Lee, J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.28.538700 · Cited by 4
Self-citationTandem MutSβ binding to long extruded DNA trinucleotide repeats underpins pathogenic expansionsPreprint
Li, J., Wang, H., & Yang, W. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.12.571350 · Cited by 5
Belgrad, J., Tang, Q., Hildebrand, S. R., Summers, A., Sapp, E., Echeverria, D., O’Reilly, D., Luu, E., Bramato, B. M., Allen, S. E., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.19.572404 · Cited by 4
Lowering the HTT1a transcript as an effective therapy for Huntington’s diseasePreprint
Papadopoulou, A. S., Alterman, J. F., Landles, C., Smith, E. J., Conroy, F., Phillips, J. M., Cañibano-Pico, M., Nita, I. M., Osborne, G. F., Iqbal, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.10.658804 · Cited by 4
Li, J., Lin, Y., Gao, J., Yang, F., Li, C., Chen, Y., Huang, C., Song, X., Song, Z., Wu, J., et al. (2026) · Nature Biomedical Engineering · doi:10.1038/s41551-026-01621-x · Cited by 3
Genetic mouse models to explore Huntington's disease mechanisms and therapeutic strategies
Gray, M., Zeitlin, S. O., Moran-Reyna, A., & Liu, J.-P. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95672-7.00013-3 · Cited by 3
Functional Specifics of the MutL Protein of the DNA Mismatch Repair System in Different Organisms
Monakhova, M. V., Милакина, М. А., Trikin, R. M., Oretskaya, T. S., & Kubareva, E. A. (2020) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162020060217 · Cited by 3
Vnencak‐Jones, C. L., & Best, D. H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-816061-9.00006-0 · Cited by 3
Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models
Tomé, S., & Dandelot, E. (2017) · InTech eBooks · doi:10.5772/66438 · Cited by 3
Gomes-Pereira, M., & Monckton, D. G. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.606331 · Cited by 3
“However, unlike MLH3 (Pinto et al., 2013), PMS2 is not essential for expansion (Gomes-Pereira et al., 2004b).”
BackgroundInfluentialFerguson, R., Goold, R., Coupland, L. A., Flower, M. D., & Tabrizi, S. J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.05.570095 · Cited by 3
Guevara‐Ramírez, P., Ruiz‐Pozo, V. A., Cadena-Ullauri, S., Paz‐Cruz, E., Tamayo‐Trujillo, R., Gaviria, A., Cevallos, F., & Zambrano, A. K. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1498290 · Cited by 2
Casazza, K., Williams, G. M., Johengen, L., Twoey, G., & Surtees, J. A. (2025) · Genetics · doi:10.1093/genetics/iyae222 · Cited by 2
“Both MutL α and MutL γ promote TNR expansions in vivo in mammalian systems in a Msh2-Msh3-specific manner (Pinto et al .”
Jimenez, D. A., Walker, A. K., Usdin, K., & Zhao, X.-N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062655 · Cited by 2
“FANCJ also interacts with MLH1, a protein required for repeat expansion [25,54,55], in both the repair of ICLs [56] and in MMR [57–59].”
ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin
Perry, C. M., & Martin, D. D. O. (2026) · Journal of Neuroscience · doi:10.1523/jneurosci.0263-25.2026 · Cited by 2
Belgrad, J., Summers, A., Landles, C., Greene, J. R., Hildebrand, S. R., Knox, E. G., Sapp, E., Yamada, N., Furgal, R. C., Miller, R., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.aea3104 · Cited by 2
Hayward, B. E., Kim, G.-Y., Miller, C. J., McCann, C., Lowery, M. G., Wood, R. D., & Usdin, K. (2025) · Scientific Reports · doi:10.1038/s41598-025-87541-3 · Cited by 2
Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?
Mannan, A., Sharma, A., & Singh, T. G. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05263-z · Cited by 2
“Notably, genetic variants that enhance FAN1 expression and function are associated with a later onset and slower progression of HD, while variants that reduce its activity tend to accelerate the disease progression [178].”
Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways
Ratovitski, T., Holland, C. D., O’Meally, R. N., Shevelkin, A. V., Kamath, S. V., Shi, T., Rodriguez, M., Cole, R. N., Jiang, M., & Ross, C. A. (2026) · Life Science Alliance · doi:10.26508/lsa.202503424 · Cited by 2
“Although we find that HTT interacts with several proteins involved with DNA repair, it is notable that there appears to be little or no interaction with the proteins encoded by genetic modifier loci (17, 18, 19, 20, 21, 22, 23, 80), many of which are specifically involved in mismatch repair.”
SPYing on triplet repeat expansions: Insights into FAN1-MLH1 interaction and regulation
Lahue, R. S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109736 · Cited by 2
Cho, I. K., Clever, F., Hong, G., & Chan, A. W. S. (2022) · Biomedicines · doi:10.3390/biomedicines10081863 · Cited by 2
“Additionally, the trend of gene expressions that have been associated with HD pathogenesis and CAG repeat expansions, such as huntingtin (HTT), huntingtininteracting protein 1 (HIP1), 8-oxoguanine DNA glycosylase (OGG1) [61], tumor protein 53 (TP53) [66,67], RE1-silencing transcription factor (REST) [68], nuclear fact…”
BackgroundMechanisms of somatic CAG-repeat expansions in Huntington's disease
Deshmukh, A. L., Gall-Duncan, T., & Pearson, C. E. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95672-7.00002-9 · Cited by 2
Self-citationUsing Genomic Data to Find Disease-Modifying Loci in Huntington’s Disease (HD)
Holmans, P., & Stone, T. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7825-0_20 · Cited by 2
Choi, D. E., Shin, J. W., Zeng, S., Hong, E. P., Jang, J.-H., Loupe, J. M., Wheeler, V. C., Stutzman, H. E., Kleinstiver, B. P., & Lee, J. (2023) · eLife · doi:10.7554/elife.89782.1 · Cited by 2
Self-citation
Metadata
- Authors
- Pinto, R. M., Dragileva, E., Kirby, A., Lloret, A., Lopez, E., St. Claire, J., Panigrahi, G. B., Hou, C., Holloway, K., Gillis, T., Guide, J. R., Cohen, P. E., Li, G.-M., Pearson, C. E., Daly, M. J., & Wheeler, V. C.
- Affiliations
- Massachusetts General Hospital (US)
- Broad Institute (US)
- University of Toronto (CA)
- University of Kentucky (US)
- Cornell University (US)
- Corresponding author
- Wheeler, Vanessa C.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-31
- Volume
- 9
- Issue
- 10
- Pages
- e1003930
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3814320
- OpenAlex
- W2107416433
- Cited by
- 250
- References
- 100
- Citations by year
- 2026: 20 · 2025: 24 · 2024: 32 · 2023: 26 · 2022: 12 · 2021: 30 · 2020: 27 · 2019: 8 · 2018: 19 · 2017: 16 · 2016: 17 · 2015: 11 · 2014: 7
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM089684, GM089684, R01GM097263)
- National Institute of Neurological Disorders and Stroke (NS049206, R01NS049206)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00HD065870)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Huntington's disease, CAG repeat instability, somatic repeat expansion, DNA mismatch repair, MLH1, MLH3, MSH2, MSH3, genetic modifiers, strain differences, striatum, DNA repair
- MeSH terms
- MutL Proteins, MutL Protein Homolog 1, Animals, Carrier Proteins, Disease Models, Animal, Humans, Huntington Disease, Nuclear Proteins, RNA, Messenger, Trinucleotide Repeat Expansion, Genomic Instability, Adaptor Proteins, Signal Transducing, Mice, Genome-Wide Association Study, Genetic Association Studies
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