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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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Sequence-based characterization of structural variation in the mouse genome
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“Importantly, we find that the MutL c components, MLH1 and MLH3, are as critical to somatic Hdh Q111 CAG expansion as the MutS b components MSH2 and MSH3 [18,19], suggesting that MutL c and MutS b are involved in the same pathway that promotes CAG/CTG expansion.”
BackgroundMethodInfluentialSelf-citationMismatch repair gene Msh2 modifies the timing of early disease in HdhQ111 striatum
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“Importantly, we find that the MutL c components, MLH1 and MLH3, are as critical to somatic Hdh Q111 CAG expansion as the MutS b components MSH2 and MSH3 [18,19], suggesting that MutL c and MutS b are involved in the same pathway that promotes CAG/CTG expansion.”
BackgroundInfluentialSelf-citationDNA instability in postmitotic neurons
Gonitel, R., Moffitt, H., Sathasivam, K., Woodman, B., Detloff, P., Faull, R., & Bates, G. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0800048105 · Cited by 225 · cited 1×
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“mediated expansion arising via other pathways that are MutLindependent, such as single strand annealing [23,61].”
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Seong, I. S., Woda, J. M., Song, J., Lloret, A., Abeyrathne, P. D., Woo, C. J., Gregory, G. C., Lee, J., Wheeler, V. C., Walz, T., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp524 · Cited by 193 · cited 1×
“Full-length Mlh1 cDNAs were amplified by PCR (for primers used see Table S2) using Phusion High-Fidelity DNA polymerase (New England Biolabs), and were subsequently cloned between the unique NcoI and XhoI sites of a modified pFastBac1 baculovirus expression vector [88], so that the resulting recombinant MLH1 proteins…”
MethodSelf-citationThe FANCJ/MutLα interaction is required for correction of the cross‐link response in FA‐J cells
Peng, M., Litman, R., Xie, J., Sharma, S., Brosh, R. M., & Cantor, S. B. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601754 · Cited by 181
MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice
Tomé, S., MANLEY, K. M., Simard, J. P., Clark, G. W., Slean, M. M., Swami, M., Shelbourne, P., Tillier, E. R. M., Monckton, D. G., Messer, A. C., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003280 · Cited by 172 · cited 7×
“Interestingly, Msh3 gene variants were recently found to correlate with HTT CAG instability in some strains of R6/1 transgenic mice [29].”
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“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
ResultSelf-citationFoiry, L., Dong, L., Savouret, C., Hubert, L., Riele, H. T., Junien, C., & Gourdon, G. (2006) · Human Genetics · doi:10.1007/s00439-006-0164-7 · Cited by 151 · cited 20×
“However, at least for the B6N and 129S2 strains in which we have performed genome-wide QTL mapping, it is clear from the genetic data that any polymorphisms in the Msh3 gene do not play a significant role in driving these strain-specific differences in somatic expansion of the Hdh Q111 CAG repeat (Figure 2B).”
BackgroundInfluentialNoncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
Peña-Dı́az, J., Bregenhorn, S., Ghodgaonkar, M. M., Follonier, C., Borán, M. S., Castor, D., Lopes, M., Sartori, A. A., & Jiricny, J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.07.006 · Cited by 150 · cited 1×
“promutagenic noncanonical MMR pathway has been described, which occurs in multiple cell types, is independent of DNA replication and is activated by DNA lesions rather than mismatches [70].”
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“However, there is increasing evidence that MMR proteins play various roles in the absence of DNA replication and participate in a variety of other pathways, distinct from MMR [64–69].”
BackgroundA novel approach to investigate tissue-specific trinucleotide repeat instability
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“Hdh striata using a previously described method [32].”
MethodSelf-citationFactors associated with HD CAG repeat instability in Huntington disease
Wheeler, V. C., Persichetti, F., McNeil, S. M., Mysore, J. S., Mysore, S. S., MacDonald, M. E., Myers, R. H., Gusella, J. F., & Wexler, N. S. (2007) · Journal of Medical Genetics · doi:10.1136/jmg.2007.050930 · Cited by 146 · cited 1×
“The expanded HTT CAG repeat is highly unstable both in the germline and in somatic tissues [6–13].”
BackgroundSelf-citationHuman MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases
Pearson, C. E. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.7.1117 · Cited by 144 · cited 1×
“CAGNCTG repeat structures are initially recognized by the MutSb (MSH2-MSH3) complex [25,98].”
BackgroundSelf-citationFunctional Analysis of Human MLH1 Variants Using Yeast and In vitro Mismatch Repair Assays
Takahashi, M., Shimodaira, H., Andreutti-Zaugg, C., Iggo, R. D., Kolodner, R. D., & Ishioka, C. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3509 · Cited by 139 · cited 1×
“Note that as mMLH1-hPMS2 was functional in this well-established human-based assay, consistent with previous mixed yeast-human MMR assays [90–92], we compared B6 and 129 MLH1 proteins in a mixed mouse-human MutL a complex, avoiding the need to introduce mouse PMS2 as another assay variable.”
ResultNoncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
Peña-Dı́az, J., Bregenhorn, S., Ghodgaonkar, M. M., Follonier, C., Borán, M. S., Castor, D., Lopes, M., Sartori, A. A., & Jiricny, J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.026 · Cited by 132
A Genome Scan for Modifiers of Age at Onset in Huntington Disease: The HD MAPS Study
Li, J.-L., Hayden, M. R., Almqvist, E. W., Brinkman, R. R., Durr, A., Dodé, C., Morrison, P. J., Suchowersky, O., Ross, C. A., Margolis, R. L., et al. (2003) · The American Journal of Human Genetics · doi:10.1086/378133 · Cited by 126 · cited 1×
“evidence supporting the contribution of genetic factors [3,4].”
BackgroundSelf-citationExpression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair
Cannavò, E., Marra, G., Sabates–Bellver, J., Menigatti, M., Lipkin, S. M., Fischer, F., Ćejka, P., & Jiricny, J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2528 · Cited by 125 · cited 4×
“As shown previously [50], complementation of MLH1-and PMS2-deficient HEK293T cells with wild-type human MutL a restored repair activity (Figure 8A).”
MethodInfluentialMouse models for human DNA mismatch-repair gene defects
Wei, K., Kucherlapati, R., & Edelmann, W. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02359-6 · Cited by 124 · cited 2×
“Conversely, MSH6 and PMS2 play prominent roles in classical MMR [72–74].”
BackgroundHuntington's disease: the case for genetic modifiers
Gusella, J. F., & MacDonald, M. E. (2009) · Genome Medicine · doi:10.1186/gm80 · Cited by 120 · cited 1×
“pursued via a number of candidate and global genetic approaches [5].”
BackgroundCoordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion
Liu, Y., Prasad, R., Beard, W. A., Hou, E. W., Horton, J. K., McMurray, C. T., & Wilson, S. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.050286 · Cited by 118 · cited 1×
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
ResultMSH2 ATPase Domain Mutation Affects CTG•CAG Repeat Instability in Transgenic Mice
Tomé, S., Holt, I., Edelmann, W., Morris, G. E., Münnich, A., Pearson, C. E., & Gourdon, G. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000482 · Cited by 114
Self-citationMammalian mismatch repair: error-free or error-prone?
Peña-Dı́az, J., & Jiricny, J. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.03.001 · Cited by 109
Fine mapping in 94 inbred mouse strains using a high-density haplotype resource
Kirby, A., Kang, H. M., Wade, C. M., Cotsapas, C., Kostem, E., Han, B., Furlotte, N., Kang, E. Y., Rivas, M., Bogue, M. A., et al. (2010) · Genetics · doi:10.1534/genetics.110.115014 · Cited by 102 · cited 5×
“In an attempt to primarily enhance resolution at this QTL, but also to specifically investigate the Mlh1 gene, we genotyped the F2 animals for 10 additional markers distributed across the QTL region, including two markers located within the Mlh1 gene (Figure S3 and Table S1).”
MethodInfluentialSelf-citationRaamsdonk, J. M. V., Metzler, M., Slow, E., Pearson, J., Schwab, C., Carroll, J. B., Graham, R. K., Leavitt, B. R., & Hayden, M. R. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.010 · Cited by 101
Chen, P., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., Yoon, S., Yang, K., Arnheim, N., Liskay, R. M., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0742 · Cited by 100
Lloret, A., Dragileva, E., Teed, A. M., Espinola, J. A., Fossale, E., Gillis, T., Lopez, E., Myers, R. H., MacDonald, M. E., & Wheeler, V. C. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl125 · Cited by 92 · cited 9×
“In concordance with our previous qualitative assessment [17], the quantification of instability in striatum and”
BackgroundResultInfluentialSelf-citationPanigrahi, G. B., Slean, M. M., Simard, J. P., Gileadi, O., & Pearson, C. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909087107 · Cited by 91 · cited 2×
“We then tested the ability of B6 and 129 MLH1 proteins to repair a single CTG slip-out (CAG)47N(CTG)48 [50,51], a potential intermediate in the expansion process, as requirements for processing of slipped-DNAs formed by trinucleotide repeats may more closely resemble those that ultimately result in CAG expansion in mi…”
BackgroundMethodSelf-citationFunctional Characterization of Pathogenic Human MSH2 Missense Mutations in Saccharomyces cerevisiae
Gammie, A. E., Erdeniz, N., Beaver, J. A., Devlin, B., Nanji, A., & Rose, M. D. (2007) · Genetics · doi:10.1534/genetics.107.071084 · Cited by 89 · cited 1×
“Note that as mMLH1-hPMS2 was functional in this well-established human-based assay, consistent with previous mixed yeast-human MMR assays [90–92], we compared B6 and 129 MLH1 proteins in a mixed mouse-human MutL a complex, avoiding the need to introduce mouse PMS2 as another assay variable.”
ResultKovalenko, M. V., Dragileva, E., Claire, J. S., Gillis, T., Guide, J. R., New, J., Dong, H., Kucherlapati, R., Kucherlapati, M. H., Ehrlich, M. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044273 · Cited by 88 · cited 6×
“Importantly, we find that the MutL c components, MLH1 and MLH3, are as critical to somatic Hdh Q111 CAG expansion as the MutS b components MSH2 and MSH3 [18,19], suggesting that MutL c and MutS b are involved in the same pathway that promotes CAG/CTG expansion.”
BackgroundInfluentialSelf-citationLee, J., Pinto, R. M., Gillis, T., Claire, J. S., & Wheeler, V. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023647 · Cited by 87 · cited 3×
“Hdh mice [33], we also quantified instability indices in B6.”
BackgroundMethodSelf-citationA Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases
Kaplan, S., Itzkovitz, S., & Shapiro, E. Y. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030235 · Cited by 81 · cited 1×
“Mathematical modeling has suggested a mechanism by which somatic expansion beyond a threshold repeat length is required for clinical onset [14].”
BackgroundPluciennik, A., Burdett, V., Baitinger, C., Iyer, R. R., Shi, K. X., & Modrich, P. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311325110 · Cited by 77 · cited 1×
“activity of PMS2 [62], which, interestingly, is activated by extrahelical CAG/CTG repeats in vitro [63].”
BackgroundNovel and diverse functions of the DNA mismatch repair family in mammalian meiosis and recombination
Kolas, N. K., & Cohen, P. E. (2004) · Cytogenetic and Genome Research · doi:10.1159/000080600 · Cited by 77 · cited 1×
“in the absence of DNA replication and participate in a variety of other pathways, distinct from MMR [64–69].”
BackgroundSelf-citationMøllersen, L., Rowe, A. D., Illuzzi, J. L., Hildrestrand, G. A., Gerhold, K. J., Tveterås, L., Bjølgerud, A., Wilson, D. M., Bjørås, M., & Klungland, A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds337 · Cited by 74 · cited 1×
“Other members of alternative DNA repair pathways, namely OGG1, XPA and NEIL1 have been directly implicated in CAG/CTG somatic instability in mice [76–78], however, how these proteins intersect with MMR protein-dependent pathways has yet to be demonstrated. doi:10.1371/journal.pgen.1003930.g011 was…”
BackgroundInfluentialHubert, L., Lin, Y., Dion, V., & Wilson, J. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr421 · Cited by 74 · cited 2×
“Other members of alternative DNA repair pathways, namely OGG1, XPA and NEIL1 have been directly implicated in CAG/CTG somatic instability in mice [76–78], however, how these proteins intersect with MMR protein-dependent pathways has yet to be demonstrated.”
BackgroundHall, M. C., Shcherbakova, P. V., & Kunkel, T. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106120200 · Cited by 73 · cited 2×
“though outside conserved ATP binding motifs [46]; E390D and”
BackgroundSomatic expansion of the (CAG) n repeat in Huntington disease brains
de Rooij, K. E., Gans, P. A. M. D. K., Roos, R. A. C., van Ommen, G. B., & den Dunnen, J. T. (1995) · Human Genetics · doi:10.1007/bf00225192 · Cited by 68
Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops
Lang, W. H., Coats, J. E., Majka, J., Hura, G. L., Lin, Y., Rasnik, I., & McMurray, C. T. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105461108 · Cited by 67 · cited 1×
“role for proteins downstream of MutL complexes in somatic CAG/CTG expansion has not been demonstrated to date, the requirements for MLH1 and MLH3 indicate that the generation of somatic Hdh CAG expansions requires active engagement of the MMR machinery, in contrast to a model whereby expansions occur due to the inabil…”
BackgroundLander, E. S., Green, P., Abrahamson, J., Barlow, A., Daly, M. J., Lincoln, S. E., & Newberg, L. A. (2009) · Genomics · doi:10.1016/j.ygeno.2008.12.003 · Cited by 67
Self-citationEzzatizadeh, V., Pinto, R. M., Sandi, C., Sandi, M., Al‐Mahdawi, S., Riele, H. T., & Pook, M. A. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.01.002 · Cited by 62 · cited 1×
“Given evidence suggesting a role for MMR pathways in both somatic and intergenerational repeat instability [18,23,59], it is plausible that genetic variation at the Mlh1 locus also underlies the difference in intergenerational instability between the two strains.”
BackgroundSelf-citationPms2 Suppresses Large Expansions of the (GAA·TTC)n Sequence in Neuronal Tissues
Bourn, R. L., Biase, I. D., Pinto, R. M., Sandi, C., Al‐Mahdawi, S., Pook, M. A., & Bidichandani, S. I. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047085 · Cited by 56 · cited 2×
“While the effects of MMR proteins on instability can vary according to the repeat sequence and its context [21–28], it is notable that Msh2 and Msh3 enhance CAG/ CTG expansion both in HD and DM1 mouse models [18–23, 25– 27 ], An alternative approach for identifying modifiers in the mouse is to take…”
BackgroundResultSelf-citationSlean, M. M., Panigrahi, G. B., Ranum, L. P. W., & Pearson, C. E. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.03.014 · Cited by 54 · cited 1×
“However, there is increasing evidence that MMR proteins play various roles in the absence of DNA replication and participate in a variety of other pathways, distinct from MMR [64–69].”
BackgroundSelf-citationVeitch, N., Ennis, M., McAbney, J. P., Shelbourne, P., & Monckton, D. G. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.01.002 · Cited by 52 · cited 1×
“expansion that occurs between HD patients [9,11].”
Lin, Y., & Wilson, J. H. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.04.024 · Cited by 52 · cited 1×
“MLH1 has been found to play a role in CAG repeat instability in a selectable cell-based system [58].”
BackgroundLópez, A., Tomkinson, A. E., & Pearson, C. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.034405 · Cited by 43 · cited 1×
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
ResultSelf-citationGoula, A.-V., Pearson, C. E., Della-Maria, J., Trottier, Y., Tomkinson, A. E., Wilson, D. M., & Mérienne, K. (2012) · Biochemistry · doi:10.1021/bi300410d · Cited by 41
Self-citationPanigrahi, G. B., Slean, M. M., Simard, J. P., & Pearson, C. E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.420398 · Cited by 40 · cited 7×
“Repair of a single trinucleotide repeat slip-out by MLH1 was investigated as previously described [50].”
BackgroundMethodInfluentialSelf-citationTomé, S., Simard, J. P., Slean, M. M., Holt, I., Morris, G. E., Wojciechowicz, K., Riele, H. T., & Pearson, C. E. (2012) · DNA repair · doi:10.1016/j.dnarep.2012.10.006 · Cited by 37 · cited 2×
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
BackgroundResultSelf-citationEvidence that hMLH3 functions primarily in meiosis and in hMSH2-hMSH3 mismatch repair
Charbonneau, N., Amunugama, R., Schmütte, C., Yoder, K. E., & Fishel, R. A. (2009) · Cancer Biology & Therapy · doi:10.4161/cbt.8.14.8886 · Cited by 30 · cited 5×
“in interaction with MSH3, EXOI, MLH3, PMS1 and PMS2 [41]”
BackgroundInfluentialMutL: conducting the cell's response to mismatched and misaligned DNA
Polosina, Y. Y., & Cupples, C. G. (2009) · BioEssays · doi:10.1002/bies.200900089 · Cited by 28 · cited 2×
“enzymatic processing of the DNA mismatch [37,38].”
BackgroundPlaschke, J., Preußler, M., Ziegler, A., & Schackert, H. K. (2012) · International Journal of Colorectal Disease · doi:10.1007/s00384-011-1408-0 · Cited by 23 · cited 1×
“Withregard to potential mechanisms of CAG expansion it is of interest that MSH3 and MLH3 appear to play relatively minor roles in classical MMR inasmuch as Msh3 and Mlh3 deficiencies result in weak mutator phenotypes and relatively low cancer predisposition phenotypes [42,72–75].”
BackgroundPolosina, Y. Y., & Cupples, C. G. (2010) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2010.07.002 · Cited by 21
Cowin, R.-M., Bui, N., Graham, D. F., Green, J. R., Yuva‐Paylor, L. A., Weiss, A., & Paylor, R. E. (2012) · Mammalian Genome · doi:10.1007/s00335-012-9391-5 · Cited by 12 · cited 1×
“ences in trinucleotide repeat instability [17,22,29] and various HD mouse model phenotypes [17,30,31] have been identified.”
BackgroundAldred, P. M. R., & Borts, R. H. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351525 · Cited by 12 · cited 1×
“Note that as mMLH1-hPMS2 was functional in this well-established human-based assay, consistent with previous mixed yeast-human MMR assays [90–92], we compared B6 and 129 MLH1 proteins in a mixed mouse-human MutLa complex, avoiding the need to introduce mouse PMS2 as another assay variable.”
Result
Flagged first, then by citations
Research works printed but not linked: 2
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- Lincoln SE, Daly MJ, Lander ES (1993) Mapping Genes Controlling Quantitative Traits Using MAPMAKER/QTL Version 1.1: A Tutorial and Reference Manual. Whitehead Institute for Biomedical Research Technical Report, 2nd edition.
Cited by
Sorted by citations
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641
Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
Lee, J.-M., Wheeler, V. C., Chao, M. J., Vonsattel, J. P. G., Pinto, R. M., Lucente, D., Abu-Elneel, K., Ramos, E. M., Mysore, J. S., Gillis, T., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.003 · Cited by 655
“coli DNA mismatch repair gene mutL), whose mouse homolog, Mlh1, was discovered in a genome-wide genetic screen to modify somatic instability of the CAG repeat and the timing of CAG length-dependent phenotypes in the striatum of genetic HD replica CAG knockin mice (Pinto et al., 2013).”
Self-citationHuntington disease: new insights into molecular pathogenesis and therapeutic opportunities
Tabrizi, S. J., Flower, M. D., Ross, C. A., & Wild, E. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0389-4 · Cited by 568
CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset
Lee, J., Correia, K., Loupe, J. M., Kim, K., Barker, D., Hong, E. P., Chao, M. J., Long, J. D., Lucente, D. E., Vonsattel, J. P., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.036 · Cited by 543
“, 1999), and this process is modified by DNA maintenance genes (Dragileva et al., 2009; Pinto et al., 2013; Wheeler et al., 2003).”
Self-citationMolecular mechanisms underlying nucleotide repeat expansion disorders
Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00382-6 · Cited by 363
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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