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Darren G. Monckton - One of the best experts on this subject based on the ideXlab platform.
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PMS2 is a genetic enhancer of trinucleotide cag ctg repeat somatic mosaicism implications for the mechanism of triplet repeat expansion
Human Molecular Genetics, 2004Co-Authors: Mario Gomespereira, Laura Ingram, John P. Mcabney, Teresa M Fortune, Darren G. MoncktonAbstract:The expansion of CAG.CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice deficient for the PMS2 MMR gene. PMS2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by approximately 50% in PMS2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between PMS2(+/+) and PMS2(+/-) mice, indicating that a single functional PMS2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilization of secondary structures, but by inappropriate DNA MMR.
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PMS2 is a genetic enhancer of trinucleotide CAG·CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion
Human molecular genetics, 2004Co-Authors: Mário Gomes-pereira, M. Teresa Fortune, Laura Ingram, John P. Mcabney, Darren G. MoncktonAbstract:The expansion of CAG.CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice deficient for the PMS2 MMR gene. PMS2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by 50% in PMS2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between PMS2 1/1 and PMS2 1/2 mice, indicating that a single functional PMS2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilization of secondary structures, but by inappropriate DNA MMR.
Mark Clendenning - One of the best experts on this subject based on the ideXlab platform.
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Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort
BMJ open, 2016Co-Authors: Christophe Rosty, Michael Walsh, Mark Clendenning, Finlay A. Macrae, Stine V Eriksen, Melissa C. Southey, Ingrid Winship, Alex Boussioutas, Nicola Poplawski, Susan ParryAbstract:Objectives Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2 , previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression. Design This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification). Results Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1 . The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression. Conclusions A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified.
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PMS2 monoallelic mutation carriers: the known unknown
Genetics in medicine : official journal of the American College of Medical Genetics, 2015Co-Authors: Mckinsey L. Goodenberger, Leigha Senter, Mark Clendenning, Brittany C. Thomas, Douglas L. Riegert-johnson, C. Richard Boland, Sharon E. Plon, Aung Ko Win, Steven M. Lipkin, Zsofia K. StadlerAbstract:Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors’ research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance. Genet Med 18 1, 13–19.
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Detection of large scale 3′ deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything?
Familial cancer, 2013Co-Authors: Mark Clendenning, Michael Walsh, Stephen N Thibodeau, John D. Potter, Noralane M. Lindor, Judith Balmana Gelpi, Polly A. Newcomb, Loic Lemarchand, Robert W. Haile, Steve GallingerAbstract:Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3' end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3' end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3' deletions in PMS2 are not a frequent occurrence in such families.
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detection of large scale 3 deletions in the PMS2 gene amongst colon cfr participants have we been missing anything
Familial Cancer, 2013Co-Authors: Mark Clendenning, Michael Walsh, Stephen N Thibodeau, John D. Potter, Noralane M. Lindor, Judith Balmana Gelpi, Polly A. Newcomb, Loic Lemarchand, Robert W. Haile, Steve GallingerAbstract:Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3' end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3' end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3' deletions in PMS2 are not a frequent occurrence in such families.
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Absence of PMS2 mutations in colon-CFR participants whose colorectal cancers demonstrate unexplained loss of MLH1 expression
Clinical genetics, 2012Co-Authors: Mark Clendenning, John D. Potter, Robert W. Haile, Steve Gallinger, Finlay A. Macrae, Walsh, Rhiannon J. Walters, S N Thibodeau, Shanaka R. Gunawardena, John L. HopperAbstract:To the Editor: Lynch syndrome (LS) (MIM#276300) is a cancer predisposition condition resulting from mutations within the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2). In a suspected LS family, tumors are assessed for microsatellite instability (MSI) and/or immunohistochemical (IHC) absence of MMR proteins, both of which are hallmarks of LS. To enable appropriate diagnosis, counseling and surveillance, the gene indicated by the IHC profile is screened for mutations via techniques such as denaturing high pressure liquid chromatography (DHPLC), sequencing and multiplex ligation-dependent probe amplification (MLPA). Using these approaches, mutations are identified in the majority of cases suspected of LS; however, there remain a substantial proportion of families for which mutations cannot be identified. Tumors with loss of both MLH1 and PMS2 expression are associated with mutations in MLH1, whereas mutations in PMS2 are associated with solitary loss of PMS2. Contrary to conventional IHC indications, Niessen et al. (2009) [1] identified a PMS2 mutation (p.Q233X) in an individual whose tumor showed loss of expression of MLH1, suggesting that such mutations may explain some of these suspected LS cases. Evidence for this would necessitate a change to routine screening practices which currently have little justification to extend mutation detection beyond the primary indicated MMR gene. We screened a cohort of individuals from the Colorectal Cancer Family Registry (C-CFR; http://epi.grants.cancer.gov/CFR) whose tumors showed loss of expression of MLH1 (and PMS2), but who had not had a genetic or epigenetic MLH1 mutation identified. The C-CFR comprises 435 probands whose tumors demonstrate IHC loss of MLH1, with a causative mutation/methylation being identified in 339 (78%) cases. DNA was available for 84 of the outlying samples, which comprised the study cohort. Forty-nine of these samples had previously only been screened for MLH1 mutations via DHPLC. Subsequent sequencing analysis identified MLH1 mutations in four individuals (4/49, 8.2%) who were removed from the rest of the study. The remaining 80 individuals had a mean age of diagnosis of 47yrs, and were primarily from population-based recruitment (68/80, 85%). A history of cancer fulfilling established clinical criteria [2] was reported for 76 of the 80 probands (95%). Complete sequencing and MLPA (P008-A1) analysis (described in [3]) of the PMS2 gene in these individuals identified common polymorphisms, four rare/novel variants but no truncating mutations (Table 1). The results from this study, the only one to date that has focused on this select group of individuals, found no evidence for deleterious mutations in PMS2. As such, these findings are sufficient to exclude PMS2 as a gene for mutation testing in individuals with suspected LS based on tumoral loss of both MLH1 and PMS2 expression. This conclusion is supported by earlier studies that screened moderate numbers (n=25) of LS suspected patients showing loss of both PMS2 and MLH1, [4, 5] again with no evidence of deleterious mutations in PMS2. Table 1 Summary of the PMS2 variants identified among the 80 individuals tested The heterodimeric nature of the MMR proteins has led to the well established practice of utilizing IHC to direct mutation screening. As such, the identification of a single PMS2 mutation carrier with loss of expression of MLH1 should not give strong reason to screen PMS2 in cases with concomitant loss of MLH1 and PMS2 in the tumor when routine screening fails to identify a mutation in MLH1. [1] It is far more logical to expect either an overlooked mutation (our finding that DHPLC can miss mutations in the MLH1 gene highlights one example of how this may occur) within the coding region of MLH1 or a more complicated mutational mechanism that would not be detected by routine screening practices. [6–8] In conclusion, we have found no evidence to support screening of the PMS2 gene for mutations in CRC cases that demonstrate unexplained loss of MLH1 and PMS2. Therefore, further investigation of novel mutational mechanisms in MLH1 is warranted.
R. Michael Liskay - One of the best experts on this subject based on the ideXlab platform.
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An intact PMS2 ATPase domain is not essential for male fertility.
DNA repair, 2015Co-Authors: Jared M. Fischer, Sandra Dudley, Ashleigh J. Miller, R. Michael LiskayAbstract:Abstract The DNA mismatch repair (MMR) machinery in mammals plays critical roles in both mutation avoidance and spermatogenesis. Meiotic analysis of knockout mice of two different MMR genes, Mlh1 and Mlh3, revealed both male and female infertility associated with a defect in meiotic crossing over. In contrast, another MMR gene knockout, PMS2 ( PMS2 ko/ko ), which contained a deletion of a portion of the ATPase domain, produced animals that were male sterile but female fertile. However, the meiotic phenotype of PMS2 ko/ko males was less clear-cut than for Mlh1 - or Mlh3 -deficient meiosis. More recently, we generated a different PMS2 mutant allele ( PMS2 cre ), which results in deletion of the same portion of the ATPase domain. Surprisingly, PMS2 cre/cre male mice were completely fertile, suggesting that the ATPase domain of PMS2 is not required for male fertility. To explore the difference in male fertility, we examined the PMS2 RNA and found that alternative splicing of the PMS2 cre allele results in a predicted PMS2 containing the C-terminus, which contains the Mlh1-interaction domain, a possible candidate for stabilizing Mlh1 levels. To study further the basis of male fertility, we examined Mlh1 levels in testes and found that whereas PMS2 loss in PMS2 ko/ko mice results in severely reduced levels of Mlh1 expression in the testes, Mlh1 levels in PMS2 cre/cre testes were reduced to a lesser extent. Thus, we propose that a primary function of PMS2 during spermatogenesis is to stabilize Mlh1 levels prior to its critical crossing over function with Mlh3.
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Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance☆
Cancer letters, 2006Co-Authors: Shannon L. Gibson, Latha Narayanan, Denise C. Hegan, Andrew B. Buermeyer, R. Michael Liskay, Peter M. GlazerAbstract:Inherited defects in genes associated with DNA mismatch repair (MMR) have been linked to familial colorectal cancer. Cells deficient in MMR are genetically unstable and demonstrate a tolerance phenotype in response to certain classes of DNA damage. Some sporadic human cancers also show abnormalities in MMR gene function, typically due to diminished expression of one of the MutL homologs, MLH1. Here, we report that overexpression of the MutL homolog, human PMS2, can also cause a disruption of the MMR pathway in mammalian cells, resulting in hypermutability and DNA damage tolerance. A mouse fibroblast cell line carrying a recoverable lambda phage shuttle vector for mutation detection was transfected with either a vector designed to express hPMS2 or with an empty vector control. Cells overexpressing hPMS2 were found to have elevated spontaneous mutation frequencies at the cII reporter gene locus. They also showed an increase in the level of mutations induced by the alkylating agent, methynitrosourea (MNU). Clonogenic survival assays demonstrated increased survival of the PMS2-overexpressing cells following exposure to MNU, consistent with the induction of a damage tolerance phenotype. Similar results were seen in cells expressing a mutant PMS2 gene, containing a premature stop codon at position 134 and representing a variant found in an individual with familial colon cancer. These results show that dysregulation of PMS2 gene expression can disrupt MMR function in mammalian cells and establish an additional carcinogenic mechanism by which cells can develop genetic instability and acquire resistance to cytotoxic cancer therapies.
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Contributions by MutL Homologues Mlh3 and PMS2 to DNA Mismatch Repair and Tumor Suppression in the Mouse
Cancer research, 2005Co-Authors: Peng Chieh Chen, Norman Arnheim, Sandra Dudley, Wayne Hagen, Diana Dizon, Leslie Paxton, Denise Reichow, Song Ro Yoon, Kan Yang, R. Michael LiskayAbstract:Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of Escherichia coli MutL heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. Although MLH1/PMS2 is generally thought to have the major MutL activity, the precise contributions of each MutL heterodimer to mismatch repair functions are poorly understood. Here, we show that Mlh3 contributes to mechanisms of tumor suppression in the mouse. Mlh3 deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, Mlh3;PMS2 double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from Mlh1 -deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role for Mlh3 in gastrointestinal and extragastrointestinal tumor suppression. The data also suggest a mechanistic basis for the more severe mismatch repair–related phenotypes and cancer susceptibility in Mlh1 - versus Mlh3 - or PMS2 -deficient mice. Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair–mediated tumor suppression, therefore, provide an explanation why, among MutL homologues, only germ line mutations in MLH1 are common in hereditary non-polyposis colon cancer.
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Apoptosis and mutation in the murine small intestine: loss of Mlh1- and PMS2-dependent apoptosis leads to increased mutation in vivo.
DNA repair, 2003Co-Authors: Owen J. Sansom, R. Michael Liskay, Sandra Dudley, Stefan Mark Bishop, Helen Court, Alan Richard ClarkeAbstract:The mismatch repair (MMR) protein Msh2 has been shown to function in the apoptotic response to alkylating agents in vivo. Here, we extend these studies to the MutL homologues (MLH) Mlh1 and PMS2 by analysing the apoptotic response within the small intestine of gene targeted strains. We demonstrate significant differences between Msh2, Mlh1 and PMS2 mutations in influencing apoptotic signalling following 50 mg/kg N-methyl-nitrosourea (NMNU), with no obvious reliance upon either Mlh1 or PMS2. However, following exposure to 100 mg/kg temozolomide or lower levels of NMNU (10 mg/kg) both Mlh1- and PMS2-dependent apoptosis was observed, indicating that the apoptotic response at these levels of DNA damage is dependent on the MutL homologues. Given our ability to observe a MutLα dependence of the apoptotic response, we tested whether perturbations of this response directly translate into increases in mutation frequency in vivo. We show that treatment with temozolomide or 10 mg/kg NMNU significantly increases mutation in both the Mlh1 and PMS2 mutant mice. At higher levels of NMNU, where the apoptotic response is independent of Mlh1 and PMS2, no gene dependent increase in mutation frequency was observed. These results argue that the MutSα and MutLα are not equally important in their ability to signal apoptosis. However, when MMR does mediate apoptosis, perturbation of this response leads to long-term persistence of mutant cells in vivo.
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Contribution of Human Mlh1 and PMS2 ATPase Activities to DNA Mismatch Repair
The Journal of biological chemistry, 2002Co-Authors: Guy Tomer, Andrew B. Buermeyer, Megan M. Nguyen, R. Michael LiskayAbstract:Abstract MutLα, a heterodimer composed of Mlh1 and PMS2, is the major MutL activity in mammalian DNA mismatch repair. Highly conserved motifs in the N termini of both subunits predict that the protein is an ATPase. To study the significance of these motifs to mismatch repair, we have expressed in insect cells wild type human MutLα and forms altered in conserved glutamic acid residues, predicted to catalyze ATP hydrolysis of Mlh1, PMS2, or both. Using an in vitro assay, we showed that MutLα proteins altered in either glutamic acid residue were each partially defective in mismatch repair, whereas the double mutant showed no detectable mismatch repair. Neither strand specificity nor directionality of repair was affected in the single mutant proteins. Limited proteolysis studies of MutLα demonstrated that both Mlh1 and PMS2 N-terminal domains undergo ATP-induced conformational changes, but the extent of the conformational change for Mlh1 was more apparent than for PMS2. Furthermore, Mlh1 was protected at lower ATP concentrations than PMS2, suggesting Mlh1 binds ATP with higher affinity. These findings imply that ATP hydrolysis is required for MutLα activity in mismatch repair and that this activity is associated with differential conformational changes in Mlh1 and PMS2.
John P. Mcabney - One of the best experts on this subject based on the ideXlab platform.
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PMS2 is a genetic enhancer of trinucleotide cag ctg repeat somatic mosaicism implications for the mechanism of triplet repeat expansion
Human Molecular Genetics, 2004Co-Authors: Mario Gomespereira, Laura Ingram, John P. Mcabney, Teresa M Fortune, Darren G. MoncktonAbstract:The expansion of CAG.CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice deficient for the PMS2 MMR gene. PMS2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by approximately 50% in PMS2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between PMS2(+/+) and PMS2(+/-) mice, indicating that a single functional PMS2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilization of secondary structures, but by inappropriate DNA MMR.
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PMS2 is a genetic enhancer of trinucleotide CAG·CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion
Human molecular genetics, 2004Co-Authors: Mário Gomes-pereira, M. Teresa Fortune, Laura Ingram, John P. Mcabney, Darren G. MoncktonAbstract:The expansion of CAG.CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice deficient for the PMS2 MMR gene. PMS2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by 50% in PMS2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between PMS2 1/1 and PMS2 1/2 mice, indicating that a single functional PMS2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilization of secondary structures, but by inappropriate DNA MMR.
Laura Ingram - One of the best experts on this subject based on the ideXlab platform.
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PMS2 is a genetic enhancer of trinucleotide cag ctg repeat somatic mosaicism implications for the mechanism of triplet repeat expansion
Human Molecular Genetics, 2004Co-Authors: Mario Gomespereira, Laura Ingram, John P. Mcabney, Teresa M Fortune, Darren G. MoncktonAbstract:The expansion of CAG.CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice deficient for the PMS2 MMR gene. PMS2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by approximately 50% in PMS2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between PMS2(+/+) and PMS2(+/-) mice, indicating that a single functional PMS2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilization of secondary structures, but by inappropriate DNA MMR.
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PMS2 is a genetic enhancer of trinucleotide CAG·CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion
Human molecular genetics, 2004Co-Authors: Mário Gomes-pereira, M. Teresa Fortune, Laura Ingram, John P. Mcabney, Darren G. MoncktonAbstract:The expansion of CAG.CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice deficient for the PMS2 MMR gene. PMS2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by 50% in PMS2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between PMS2 1/1 and PMS2 1/2 mice, indicating that a single functional PMS2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilization of secondary structures, but by inappropriate DNA MMR.
