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Cynthia T Mcmurray - One of the best experts on this subject based on the ideXlab platform.
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Trinucleotide expansion in disease why is there a length threshold
Current Opinion in Genetics & Development, 2014Co-Authors: Do Yup Lee, Cynthia T McmurrayAbstract:Trinucleotide repeats (TNRs) expansion disorders are severe neurodegenerative and neuromuscular disorders that arise from inheriting a long tract (30-50 copies) of a Trinucleotide unit within or near an expressed gene (Figure 1a). The mutation is referred to as 'Trinucleotide expansion' since the number of triplet units in a mutated gene is greater than the number found in the normal gene. Expansion becomes obvious once the number of repeating units passes a critical threshold length, but what happens at the threshold to render the repeating tract unstable? Here we discuss DNA-dependent and RNA-dependent models by which a particular DNA length permits a rapid transition to an unstable state.
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Features of Trinucleotide repeat instability in vivo
Cell Research, 2008Co-Authors: Irina V Kovtun, Cynthia T McmurrayAbstract:Unstable repeats are associated with various types of cancer and have been implicated in more than 40 neurodegenerative disorders. Trinucleotide repeats are located in non-coding and coding regions of the genome. Studies of bacteria, yeast, mice and man have helped to unravel some features of the mechanism of Trinucleotide expansion. Looped DNA structures comprising Trinucleotide repeats are processed during replication and/or repair to generate deletions or expansions. Most in vivo data are consistent with a model in which expansion and deletion occur by different mechanisms. In mammals, microsatellite instability is complex and appears to be influenced by genetic, epigenetic and developmental factors.
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Trinucleotide expansion in haploid germ cells by gap repair
Nature Genetics, 2001Co-Authors: Irina V Kovtun, Cynthia T McmurrayAbstract:Huntington disease (HD) is one of eight progressive neurodegenerative disorders in which the underlying mutation is a CAG expansion encoding a polyglutamine tract. The mechanism of Trinucleotide expansion is poorly understood. Expansion is mediated by misaligned pairing of repeats and the inappropriate formation of DNA secondary structure as the duplex unpairs. It has never been clear, however, whether duplex unpairing occurs during mitotic replication or during strand-break repair. In simple organisms, Trinucleotide expansion arises by replication slippage on either the leading or the lagging strand, homologous recombination, gene conversion, double-strand break repair and base excision repair; it is not clear which of these mechanisms is used in mammalian cells in vivo. We have followed heritable changes in CAG length in male transgenic mice. In germ cells, expansion is limited to the post-meiotic, haploid cell and therefore cannot involve mitotic replication or recombination between a homologous chromosome or a sister chromatid. Our data support a model in which expansion in the germ cells arises by gap repair and depends on a complex containing Msh2. Expansion occurs during gap-filling synthesis when DNA loops comprising the CAG Trinucleotide repeats are sealed into the DNA strand.
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dna secondary structure a common and causative factor for expansion in human disease
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Cynthia T McmurrayAbstract:The discovery of unstable transmission has changed the face of genetics because it provides an alternative to the single-gene/single-trait pattern of Mendelian inheritance. More than 10 hereditary diseases are caused by instability at simple Trinucleotides. Expansion causes disease when a particular base sequence is repeated beyond the normal range, interfering with the expression or properties of a gene product (1–2). As the length of the repeat grows, so also do the size of the successive expansions and the likelihood of another unstable event. This accounts for clinical anticipation in which the severity increases and the age of onset decreases in successive generations. In Huntington’s disease, for example, instability and pathogenesis are not observed at 28 repeats, occur frequently at 38 repeats, and are almost certain above 60 repeats. Although different genes are affected and different features of pathogenesis are evident, there is a common pattern of unstable transmission among the Trinucleotide repeat diseases, suggesting common elements to the mechanism.
Bernard Dujon - One of the best experts on this subject based on the ideXlab platform.
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replication stalling and heteroduplex formation within cag ctg Trinucleotide repeats by mismatch repair
DNA Repair, 2016Co-Authors: David Viterbo, Valentine Mosbach, Gregoire Michoud, Bernard DujonAbstract:Trinucleotide repeat expansions are responsible for at least two dozen neurological disorders. Mechanisms leading to these large expansions of repeated DNA are still poorly understood. It was proposed that transient stalling of the replication fork by the repeat tract might trigger slippage of the newly-synthesized strand over its template, leading to expansions or contractions of the triplet repeat. However, such mechanism was never formally proven. Here we show that replication fork pausing and CAG/CTG Trinucleotide repeat instability are not linked, stable and unstable repeats exhibiting the same propensity to stall replication forks when integrated in a yeast natural chromosome. We found that replication fork stalling was dependent on the integrity of the mismatch-repair system, especially the Msh2p-Msh6p complex, suggesting that direct interaction of MMR proteins with secondary structures formed by Trinucleotide repeats in vivo, triggers replication fork pauses. We also show by chromatin immunoprecipitation that Msh2p is enriched at Trinucleotide repeat tracts, in both stable and unstable orientations, this enrichment being dependent on MSH3 and MSH6. Finally, we show that overexpressing MSH2 favors the formation of heteroduplex regions, leading to an increase in contractions and expansions of CAG/CTG repeat tracts during replication, these heteroduplexes being dependent on both MSH3 and MSH6. These heteroduplex regions were not detected when a mutant msh2-E768A gene in which the ATPase domain was mutated was overexpressed. Our results unravel two new roles for mismatch-repair proteins: stabilization of heteroduplex regions and transient blocking of replication forks passing through such repeats. Both roles may involve direct interactions between MMR proteins and secondary structures formed by Trinucleotide repeat tracts, although indirect interactions may not be formally excluded.
David Viterbo - One of the best experts on this subject based on the ideXlab platform.
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replication stalling and heteroduplex formation within cag ctg Trinucleotide repeats by mismatch repair
DNA Repair, 2016Co-Authors: David Viterbo, Valentine Mosbach, Gregoire Michoud, Bernard DujonAbstract:Trinucleotide repeat expansions are responsible for at least two dozen neurological disorders. Mechanisms leading to these large expansions of repeated DNA are still poorly understood. It was proposed that transient stalling of the replication fork by the repeat tract might trigger slippage of the newly-synthesized strand over its template, leading to expansions or contractions of the triplet repeat. However, such mechanism was never formally proven. Here we show that replication fork pausing and CAG/CTG Trinucleotide repeat instability are not linked, stable and unstable repeats exhibiting the same propensity to stall replication forks when integrated in a yeast natural chromosome. We found that replication fork stalling was dependent on the integrity of the mismatch-repair system, especially the Msh2p-Msh6p complex, suggesting that direct interaction of MMR proteins with secondary structures formed by Trinucleotide repeats in vivo, triggers replication fork pauses. We also show by chromatin immunoprecipitation that Msh2p is enriched at Trinucleotide repeat tracts, in both stable and unstable orientations, this enrichment being dependent on MSH3 and MSH6. Finally, we show that overexpressing MSH2 favors the formation of heteroduplex regions, leading to an increase in contractions and expansions of CAG/CTG repeat tracts during replication, these heteroduplexes being dependent on both MSH3 and MSH6. These heteroduplex regions were not detected when a mutant msh2-E768A gene in which the ATPase domain was mutated was overexpressed. Our results unravel two new roles for mismatch-repair proteins: stabilization of heteroduplex regions and transient blocking of replication forks passing through such repeats. Both roles may involve direct interactions between MMR proteins and secondary structures formed by Trinucleotide repeat tracts, although indirect interactions may not be formally excluded.
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highly specific contractions of a single cag ctg Trinucleotide repeat by talen in yeast
PLOS ONE, 2014Co-Authors: Guyfranck Richard, David Viterbo, Varun Khanna, Valentine MosbachAbstract:Trinucleotide repeat expansions are responsible for more than two dozens severe neurological disorders in humans. A double-strand break between two short CAG/CTG Trinucleotide repeats was formerly shown to induce a high frequency of repeat contractions in yeast. Here, using a dedicated TALEN, we show that induction of a double-strand break into a CAG/CTG Trinucleotide repeat in heterozygous yeast diploid cells results in gene conversion of the repeat tract with near 100% efficacy, deleting the repeat tract. Induction of the same TALEN in homozygous yeast diploids leads to contractions of both repeats to a final length of 3–13 triplets, with 100% efficacy in cells that survived the double-strand breaks. Whole-genome sequencing of surviving yeast cells shows that the TALEN does not increase mutation rate. No other CAG/CTG repeat of the yeast genome showed any length alteration or mutation. No large genomic rearrangement such as aneuploidy, segmental duplication or translocation was detected. It is the first demonstration that induction of a TALEN in an eukaryotic cell leads to shortening of Trinucleotide repeat tracts to lengths below pathological thresholds in humans, with 100% efficacy and very high specificity.
Valentine Mosbach - One of the best experts on this subject based on the ideXlab platform.
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Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy
Current Genetics, 2019Co-Authors: Valentine Mosbach, Lucie Poggi, Guyfranck RichardAbstract:Trinucleotide repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental disorders. Slippage of the two complementary DNA strands during replication, homologous recombination or DNA repair is generally accepted as a mechanism leading to repeat length changes, creating expansions and contractions of the repeat tract. The present review focuses on recent developments on double-strand break repair involving Trinucleotide repeat tracts. Experimental evidences in model organisms show that gene conversion and break-induced replication may lead to large repeat tract expansions, while frequent contractions occur either by single-strand annealing between repeat ends or by gene conversion, triggering near-complete contraction of the repeat tract. In the second part of this review, different therapeutic approaches using highly specific single- or double-strand endonucleases targeted to Trinucleotide repeat loci are compared. Relative efficacies and specificities of these nucleases will be discussed, as well as their potential strengths and weaknesses for possible future gene therapy of these dramatic disorders.
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replication stalling and heteroduplex formation within cag ctg Trinucleotide repeats by mismatch repair
DNA Repair, 2016Co-Authors: David Viterbo, Valentine Mosbach, Gregoire Michoud, Bernard DujonAbstract:Trinucleotide repeat expansions are responsible for at least two dozen neurological disorders. Mechanisms leading to these large expansions of repeated DNA are still poorly understood. It was proposed that transient stalling of the replication fork by the repeat tract might trigger slippage of the newly-synthesized strand over its template, leading to expansions or contractions of the triplet repeat. However, such mechanism was never formally proven. Here we show that replication fork pausing and CAG/CTG Trinucleotide repeat instability are not linked, stable and unstable repeats exhibiting the same propensity to stall replication forks when integrated in a yeast natural chromosome. We found that replication fork stalling was dependent on the integrity of the mismatch-repair system, especially the Msh2p-Msh6p complex, suggesting that direct interaction of MMR proteins with secondary structures formed by Trinucleotide repeats in vivo, triggers replication fork pauses. We also show by chromatin immunoprecipitation that Msh2p is enriched at Trinucleotide repeat tracts, in both stable and unstable orientations, this enrichment being dependent on MSH3 and MSH6. Finally, we show that overexpressing MSH2 favors the formation of heteroduplex regions, leading to an increase in contractions and expansions of CAG/CTG repeat tracts during replication, these heteroduplexes being dependent on both MSH3 and MSH6. These heteroduplex regions were not detected when a mutant msh2-E768A gene in which the ATPase domain was mutated was overexpressed. Our results unravel two new roles for mismatch-repair proteins: stabilization of heteroduplex regions and transient blocking of replication forks passing through such repeats. Both roles may involve direct interactions between MMR proteins and secondary structures formed by Trinucleotide repeat tracts, although indirect interactions may not be formally excluded.
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highly specific contractions of a single cag ctg Trinucleotide repeat by talen in yeast
PLOS ONE, 2014Co-Authors: Guyfranck Richard, David Viterbo, Varun Khanna, Valentine MosbachAbstract:Trinucleotide repeat expansions are responsible for more than two dozens severe neurological disorders in humans. A double-strand break between two short CAG/CTG Trinucleotide repeats was formerly shown to induce a high frequency of repeat contractions in yeast. Here, using a dedicated TALEN, we show that induction of a double-strand break into a CAG/CTG Trinucleotide repeat in heterozygous yeast diploid cells results in gene conversion of the repeat tract with near 100% efficacy, deleting the repeat tract. Induction of the same TALEN in homozygous yeast diploids leads to contractions of both repeats to a final length of 3–13 triplets, with 100% efficacy in cells that survived the double-strand breaks. Whole-genome sequencing of surviving yeast cells shows that the TALEN does not increase mutation rate. No other CAG/CTG repeat of the yeast genome showed any length alteration or mutation. No large genomic rearrangement such as aneuploidy, segmental duplication or translocation was detected. It is the first demonstration that induction of a TALEN in an eukaryotic cell leads to shortening of Trinucleotide repeat tracts to lengths below pathological thresholds in humans, with 100% efficacy and very high specificity.
Makoto Tamai - One of the best experts on this subject based on the ideXlab platform.
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macular degeneration associated with aberrant expansion of Trinucleotide repeat of the sca7 gene in 2 japanese families
Archives of Ophthalmology, 2000Co-Authors: Toshiaki Abe, Yasuto Itoyama, T Tsuda, Madoka Yoshida, Yuko Wada, Tetsuya Kano, Makoto TamaiAbstract:Objective To evaluate the macular function of Japanese patients with a Trinucleotide repeat expansion in the spinocerebellar ataxia type 7 ( SCA7 ) gene. Methods Ophthalmic findings in patients whose DNA analysis revealed expanded alleles of the Trinucleotide repeat in the SCA7 gene were evaluated. Results Trinucleotide repeat was expanded from 40 to 48 in affected patients (control subjects, 12 repeats). Affected patients were characterized by different degrees of visual acuity decrease (0.09-0.9), a tritan axis color vision, a coarse granular appearance of the macular region on scanning laser ophthalmoscopy, depression of multifocal electroretinograms, and macular degeneration. However, pigmentary changes were not observed in the retina. The Trinucleotide repeat was longer and the onset of macular dysfunction was earlier in the younger generation. One patient in a family manifested decreased visual acuity 10 years preceding other neurologic signs. Conclusions and Clinical Relevance Patients with SCA7 mutations showed macular dysfunction or degeneration with expansion of CAG repeat in the SCA7 gene. However, the lesions were less pigmented than those previously reported. Patients also showed ophthalmologic anticipation, which has not been reported for the ocular changes in other patients who have Trinucleotide repeat expansion of the responsible genes.
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Corneal endothelial changes and Trinucleotide repeat expansion of DRPLA gene
British Journal of Ophthalmology, 1999Co-Authors: Norihiro Yamada, Makoto TamaiAbstract:Editor,—Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that manifests in a combination of chorea, myoclonus, seizure, ataxia, and dementia. It is caused by the unstable expansion of a CAG Trinucleotide repeat coding for glutamine in the DRPLA gene.1 Several other genes with an unstable Trinucleotide repeat expansion of CAG were cloned in some types of spinocerebellar degeneration (SCD). Several reports have also suggested an association between ocular changes and SCD.2 3 We report here the association of ocular changes in patients with an expanded allele of the Trinucleotide repeat of the DRPLA gene. ### CASE REPORTS A 46 year old woman (IV-2 in Fig 1) noticed gait disturbance and truncal ataxia at age 36 years. When we visited her, her general condition was very severe, and visual acuities were not examined. Pupils, ocular media, and fundus examination showed normal findings. Corneal endothelial cell density was 762 cells/mm …
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ocular changes in patients with spinocerebellar degeneration and repeated Trinucleotide expansion of spinocerebellar ataxia type 1 gene
Archives of Ophthalmology, 1997Co-Authors: Toshiaki Abe, Koji Abe, Masashi Aoki, Yasuto Itoyama, Makoto TamaiAbstract:Objective: To examine ocular changes in patients with spinocerebellar degeneration who have repeated Trinucleotide expansion in the spinocerebellar ataxia type 1 ( SCA1 ) gene. Design: Ophthalmic findings in 6 patients from 3 families whose DNA analysis revealed that they had an expanded allele of the Trinucleotide repeated in the SCA1 gene were compared with those of normal control subjects and other healthy family members. The DNA was extracted from peripheral blood lymphocytes of the neurodegenerative family and normal control subjects. Setting: University medical center. Results: Visual acuity gradually decreased in successive follow-up visits. Color vision and visual fields were gradually affected. Electroretinograms showed mild attenuation of oscillatory potentials. Corneal endothelial cell density was severely decreased from 600 to 1300 cells/mm 2 . These findings were not observed in the normal control subjects, other healthy family members, or other patients with spinocerebellar degeneration who had repeated Trinucleotide expansion of other genes. Conclusion: To the best of our knowledge, this is the first report describing the association between ocular changes in patients with spinocerebellar degeneration and gene mutation. These ocular changes were considered specific to patients who had the expanded allele of the repeated Trinucleotide in the SCA1 gene.
