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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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MethodData Analytics from Enroll‐ HD , a Global Clinical Research Platform for Huntington's Disease
Landwehrmeyer, G. B., Fitzer‐Attas, C. J., Giuliano, J. D., Gonçalves, N., Anderson, K. E., Cardoso, F., Ferreira, J. J., Mestre, T., Stout, J. C., & Sampaio, C. (2016) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12388 · Cited by 187
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BackgroundInfluentialMSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
Flower, M. D., Lomeikaite, V., Ciosi, M., Cumming, S. A., Morales, F., Lo, K., Moss, D. J. H., Jones, L., Holmans, P., Monckton, D. G., et al. (2019) · Brain · doi:10.1093/brain/awz115 · Cited by 165
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Self-citationFAN1 modifies Huntington’s disease progression by stabilizing the expanded HTT CAG repeat
Goold, R., Flower, M. D., Moss, D. J. H., Medway, C., Wood‐Kaczmar, A., André, R., Farshim, P. P., Bates, G. P., Holmans, P., Jones, L., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy375 · Cited by 150
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Gusella, J. F., MacDonald, M. E., & Lee, J. (2014) · Movement Disorders · doi:10.1002/mds.26001 · Cited by 150
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MethodA slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
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“…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).”
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“Our data have potentially significant implications for the Huntington’s disease (HD) process because MutLγ was reported to be important in driving somatic CAG repeat instability in a HD mouse model (63).”
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“…MMR genes (e.g. Msh2 , Msh3 , Mlh1 or Mlh3 ), or BER genes (e.g. Ogg1 or Neil1 ) can abrogate somatic and/or germline CAG repeat expansion and, in some cases, ameliorate HD-like phenotypes (Budworth et al., 2015; Kovalenko et al., 2012; Pinto et al., 2013; Usdin et al., 2015; Wheeler et al., 2003).”
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“In addition to Msh2 and Msh3, both Mlh1 and Mlh3 are absolutely required for somatic CAG expansion in HttQ111 mice [90], implicating MutL in this process.”
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“Previously, the ortholog of MLH1 had been discovered in a linkage study to be a modifier of somatic Htt CAG repeat instability in HD knock-in mice (12) and this finding, together with the observation that HD individuals with the earliest onset had the highest degree of brain CAG repeat expansion (13), implicated somat…”
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“Another is to modulate DNA repair activity in HD to retard somatic expansions (Dragileva et al., 2009; Pinto et al., 2013), but this might also run the risk of increasing overall genomic instability.”
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“Further analysis showed that expansions were dependent on both Mlh1 and Mlh3, implicating the MutLγ complex as a key driver of somatic CAG expansions in this mouse model (Pinto et al. 2013).”
InfluentialDe novo mutations, genetic mosaicism and human disease
Mohiuddin, M., Kooy, R. F., & Pearson, C. E. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.983668 · Cited by 69
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“It was observed earlier that CAG expansions in an HD mouse model, as well as all germ line and somatic CGG expansions in a Fragile X mouse, were dependent on MutLγ (MLH1-MLH3) [49,50].”
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MutLγ promotes repeat expansion in a Fragile X mouse model while EXO1 is protective
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“23), and other MutL homolog (MLH)-related endonucleases 24,25 , also suppresses expansion, bolstering the notion that the MMR pathway contributes to expansion.”
Zhou, Y., Kumari, D., Sciascia, N., & Usdin, K. (2016) · Molecular Autism · doi:10.1186/s13229-016-0105-9 · Cited by 52
Landles, C., Milton, R. E., Ali, N. S., Flomen, R. H., Flower, M. D., Schindler, F., Gomez-Paredes, C., Bondulich, M. K., Osborne, G. F., Goodwin, D., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa066 · Cited by 53
“This somatic instability is recapitulated in mouse models of Huntington’s disease (Mangiarini et al. , 1997) and is prevented in the absence of the mismatch repair genes Msh2 , Msh3 , Mlh1 and Mlh3 (Manley et al. , 1999; Pinto et al. , 2013; Tome et al. , 2013).”
Miller, C. J., Kim, G.-Y., Zhao, X.-N., & Usdin, K. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008902 · Cited by 49
“Expansion in a number of models, including the FXD mouse, has been shown to also require MutLγ, one of the three MutL complexes seen in mammalian cells [13, 24, 25].”
BackgroundBiological Aging and the Cellular Pathogenesis of Huntington’s Disease
Machiela, E., & Southwell, A. L. (2020) · Journal of Huntington s Disease · doi:10.3233/jhd-200395 · Cited by 54
Ament, S. A., Pearl, J. R., Grindeland, A., Claire, J. S., Earls, J. C., Kovalenko, M. V., Gillis, T., Mysore, J. S., Gusella, J. F., Lee, J., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx006 · Cited by 50
Self-citationMcLean, Z. L., Gao, D., Correia, K., Roy, J. C. L., Shibata, S., Farnum, I. N., Valdepenas-Mellor, Z., Kovalenko, M. V., Rapuru, M., Morini, E., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47485-0 · Cited by 49
“Instead, modi fi cation by these common haplotypes has been presumed to be due to sequence differences affecting PMS1 , given its relationship with those DNA repair genes where functional variationhasbeenclearlydemonstrated 23,24,41 .”
Self-citationHuntington’s disease: nearly four decades of human molecular genetics
Gusella, J. F., Lee, J., & MacDonald, M. E. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab170 · Cited by 50
“Endogenous models also linked repeat expansion to the timing of emergent phenotype (55,56), including demonstration with a naturally occurring Mlh1 variant that reduced expression levels decreased both the rate of expansion and the rate of striatal neuron pathology (57).”
BackgroundThe dual nature of mismatch repair as antimutator and mutator: for better or for worse
Bak, S. T., Sakellariou, D., & Peña-Dı́az, J. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00287 · Cited by 53
“In this regard, a role for MutLγ in TNR expansion associated with HD has recently been described (Pinto et al., 2013).”
BackgroundHalabi, A., Fuselier, K. T. B., & Grabczyk, E. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky143 · Cited by 48
“Further, MutL has been shown as necessary for all somatic expansions in an HD mouse model (50), substantiating a role for MutL that can be adapted more generally in DNA repeat expansion.”
Chromatin Regulation of DNA Damage Repair and Genome Integrity in the Central Nervous System
Pan, L., Penney, J., & Tsai, L. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.08.001 · Cited by 50
“[134] Pinto RM, Dragileva E, Kirby A, Lloret A, Lopez E, St Claire J, et al.”
Tissue specificity in DNA repair: lessons from trinucleotide repeat instability
Dion, V. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.04.005 · Cited by 49
Lokanga, R. A., Senejani, A. G., Sweasy, J. B., & Usdin, K. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005181 · Cited by 45
“Author Summary Unstable microsatellites are responsible for a number of debilitating human diseases known as the Repeat Expansion Diseases.”
BackgroundInfluentialCoordinated and Independent Roles for MLH Subunits in DNA Repair
Pannafino, G., & Alani, E. (2021) · Cells · doi:10.3390/cells10040948 · Cited by 43
“If MLH3 alone is playing a functional role, it must be doing so in a process that is distinct from MMR, trinucleotide repeat expansion, and meiotic crossover resolution, which all require intact MLH1-MLH3 complexes [20,21,34,83,85].”
BackgroundMutSβ abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions
Keogh, N., Chan, K. Y., Li, G., & Lahue, R. S. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx650 · Cited by 41
“The misrepair model is also consistent with the requirement for the MutL homologs Pms2, Mlh1 and Mlh3 in driving expansions, as evidenced by the reduced frequency of somatic expansions in knockout mice (27,47).”
Self-citationRoy, J. C. L., Vitalo, A. G., Andrew, M. A., Mota‐Silva, E., Kovalenko, M. V., Burch, Z. N., Nhu, A. M., Cohen, P. E., Grabczyk, E., Wheeler, V. C., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab152 · Cited by 42
Self-citationViterbo, D., Michoud, G., Mosbach, V., Dujon, B., & Richard, G. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.03.002 · Cited by 39
FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats
Porro, A., Mohiuddin, M., Zurfluh, C., Spegg, V., Dai, J., Iehl, F., Ropars, V., Collotta, G., Fishwick, K. M., Mozaffari, N. L., et al. (2021) · Science Advances · doi:10.1126/sciadv.abf7906 · Cited by 41
Self-citationFerguson, R., Goold, R., Coupland, L. A., Flower, M. D., & Tabrizi, S. J. (2024) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2024.04.015 · Cited by 43
“75 Despite this, the effect we observe upon lowering MLH1 expression is concordant with the reduced repeat expansion reported in multiple Mlh1 null mouse models of HD 23,39 and our previous work in a U2OS cell system.”
Martins, S., Pearson, C. E., Coutinho, P., Provost, S., Amorim, A., Dubé, M., Sequeiros, J., & Rouleau, G. A. (2014) · Human Genetics · doi:10.1007/s00439-014-1467-8 · Cited by 38
“The most studied MSH2, MSH3, PMS2, MLH1, and MLH3 are definitively involved in repeat instability, but the exact mechanism of their action remains unclear as does their relevance to humans (Ezzatizadeh et al. 2012; Pinto et al. 2013).”
BackgroundSelf-citationTALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats
Mosbach, V., Poggi, L., Viterbo, D., Charpentier, M., & Richard, G. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.083 · Cited by 38
“2146 Cell Reports 22, 2146–2159, February 20, 2018 a 2018 The Aut This is an open access article under the CC BY license (http://creative player of the expansion process, although its precise role is not totally clear (Foiry et al., 2006; Manley et al., 1999; Owen et al., 2005; Pearson et al., 1997; Pinto et al., 2013…”
BackgroundDrugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases
Benn, C., Gibson, K. R., & Reynolds, D. S. (2020) · Journal of Huntington s Disease · doi:10.3233/jhd-200421 · Cited by 35
Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs
Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J. M., Collins, R. L., Lucente, D. E., Ruliera, J., Gillis, T., et al. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddaa283 · Cited by 34
“Evidence for the rate-to-threshold component points to somatic instability of the expanded repeat, which is an area of active investigation, previously of interest in mouse models (9,10), that is now gaining traction in humans based on the identities of the DNA maintenance modifier genes with variants that produce the…”
BackgroundSelf-citationEpigenetic regulation in Huntington's disease
Hyeon, J. W., Kim, A. H., & Yano, H. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105074 · Cited by 40
Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts
Polyzos, A. A., & McMurray, C. T. (2017) · DNA repair · doi:10.1016/j.dnarep.2017.06.017 · Cited by 35
Smith, E. J., Sathasivam, K., Landles, C., Osborne, G. F., Mason, M. A., Gomez-Paredes, C., Taxy, B. A., Milton, R. E., Ast, A., Schindler, F., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcad010 · Cited by 35
Kovalenko, M. V., Milnerwood, A. J., Giordano, J. V., Claire, J. S., Guide, J. R., Stromberg, M., Gillis, T., Sapp, E., DiFiglia, M., MacDonald, M. E., et al. (2018) · Journal of Huntington s Disease · doi:10.3233/jhd-170282 · Cited by 34
“HttQ111 mice exhibit time-dependent somatic instability, with particularly high levels of expansion in the liver and striatum, correlating with cellular pathogenesis in the latter [21, 24, 39, 40].”
BackgroundSelf-citationMatuszek, Ż., Arbab, M., Kesavan, M., Hsu, A., Roy, J. C. L., Zhao, J., Yu, T., Weisburd, B., Newby, G. A., Doherty, N. J., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02172-8 · Cited by 35
“134,138).”
Self-citationLarson, E., Fyfe, I., Morton, A. J., & Monckton, D. G. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.01.004 · Cited by 38
“Most notably, mouse models have been instrumental in revealing a critical role for the Msh2, Mlh1, Mlh3, Msh3 and Pms2 DNA mismatch repair genes in mediating both somatic and germline expansions (Manley et al., 1999; Kovtun andMcMurray, 2001; van den Broek et al., 2002; Savouret et al., 2003; Gomes-Pereira et al., 200…”
InfluentialGenetic modifiers of repeat expansion disorders
Rajagopal, S., Donaldson, J., Flower, M. D., Moss, D. J. H., & Tabrizi, S. J. (2023) · Emerging Topics in Life Sciences · doi:10.1042/etls20230015 · Cited by 32
Huntington disease: somatic expansion, pathobiology and therapeutics
Donaldson, J., Moss, D. J. H., Ciosi, M., Usdin, K., Balmus, G., Monckton, D. G., & Tabrizi, S. J. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-025-01159-7 · Cited by 36
“Early studies of MMR proteins have shown that MSH2, MSH3, MLH1 and MLH3 are essential for somatic CAG repeat expansions in mice 73–75 , and knockout of Msh2 has also shown phenotypic improvements 76 .”
Neto, J. L., Lee, J., Afridi, A., Gillis, T., Guide, J. R., Dempsey, S., Lager, B., Alonso, I. D. C. M. P., Wheeler, V. C., & Pinto, R. M. (2016) · Genetics · doi:10.1534/genetics.116.195578 · Cited by 35
“…Genetic Research (CHGR)]breedingdatawereobtained for theHttQ111 lineon six background strains: CD1, B6J, C57BL/6NCrl (B6N), 129S2/ SvPasCrlf (129), FVB/NCrl (FVB) and DBA/2J (DBA); as well as forHttQ80 andHttQ92 onCD1 andB6J backgrounds (Wheeler et al. 1999; Lloret et al. 2006; Pinto et al. 2013).”
BackgroundMethodSelf-citationHayward, B. E., Steinbach, P. J., & Usdin, K. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa573 · Cited by 30
Bergonzoni, G., Döring, J., & Biagioli, M. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.628010 · Cited by 32
“Knock-out of DNA mismatch repair (MMR) proteins in HdhQ111 knock-in mice showed that Msh2/3/6, Mlh1, and Mlh3 are modifiers of somatic CAG instability (Wheeler, 2003; Dragileva et al., 2009; Pinto et al., 2013).”
BackgroundMSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo
Williams, G. M., & Surtees, J. A. (2015) · Genetics · doi:10.1534/genetics.115.177303 · Cited by 31
Recent advances in genetics of chorea
Mencacci, N. E., & Carecchio, M. (2016) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000352 · Cited by 32
Zhao, X.-N., Kumari, D., Miller, C. J., Kim, G.-Y., Hayward, B. E., Vitalo, A. G., Pinto, R. M., & Usdin, K. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200423 · Cited by 32
“MutL MLH1 ↑ [69] [107] MLH3 ↑ [59] [107] PMS1 ↑ [70] PMS2 ↑ [70] ↓ [65]”
Self-citationBelgrad, 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. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae368 · Cited by 36
Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation
Ciosi, M., Cumming, S. A., Chatzi, A., Larson, E., Tottey, W., Lomeikaite, V., Hamilton, G. M., Wheeler, V. C., Pinto, R. M., Kwak, S., et al. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200433 · Cited by 32
Self-citationLong somatic DNA-repeat expansion drives neurodegeneration in Huntington diseasePreprint
Handsaker, R. E., Kashin, S., Reed, N. M., Tan, S., Lee, W., McDonald, T. M., Morris, K., Kamitaki, N., Mullally, C. D., Morakabati, N. R., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.17.592722 · Cited by 31
FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism
Phadte, A. S., Bhatia, M., Ebert, H., Abdullah, H., Elrazaq, E. A., Komolov, K. E., & Pluciennik, A. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302103120 · Cited by 30
Activated or Impaired: An Overview of DNA Repair in Neurodegenerative Diseases
Qin, N., Geng, A., & Xue, R. (2022) · Aging and Disease · doi:10.14336/ad.2021.1212 · Cited by 31
“Initially, the mismatch site is recognized by MLH1.”
BackgroundExpanded roles for the MutL family of DNA mismatch repair proteins
Furman, C. M., Elbashir, R., & Alani, E. (2020) · Yeast · doi:10.1002/yea.3512 · Cited by 28
“Lastly, recent studies in yeast and higher eukaryotes have suggested a role for Mlh1–Mlh3 in mediating somatic CAG trinucleotide repeat instability (Pinto et al., 2013; Su & Freudenreich, 2017).”
BackgroundGall-Duncan, T., Luo, J., Jurkovic, C.-M., Fischer, L. A., Fujita, K., Deshmukh, A. L., Harding, R., Tran, S., Mehkary, M., Li, V., et al. (2023) · Cell · doi:10.1016/j.cell.2023.09.008 · Cited by 32
Self-citationCis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics
McGinty, R. J., & Mirkin, S. M. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.02.005 · Cited by 30
Akçimen, F., Martins, S., Liao, C., Bourassa, C. V., Catoire, H., Nicholson, G. A., Rieß, O., Raposo, M., França, M. C., Vasconcelos, J., et al. (2020) · Aging · doi:10.18632/aging.102825 · Cited by 27
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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