341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model
<jats:title>Abstract</jats:title><jats:p>Fragile X syndrome (FXS) is a leading monogenic cause of intellectual disability and autism spectrum disorders, spurring decades of intense research and a multitude of mouse models. So far, these models do not recapitulate the genetic underp...
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| Format: | Article |
| Language: | English |
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Society for Neuroscience
2023
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| Online Access: | https://hdl.handle.net/1721.1/148777 |
| _version_ | 1826214450222333952 |
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| author | Colvin, Steven Lea, Nick Zhang, Qiangge Wienisch, Martin Kaiser, Tobias Aida, Tomomi Feng, Guoping |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Colvin, Steven Lea, Nick Zhang, Qiangge Wienisch, Martin Kaiser, Tobias Aida, Tomomi Feng, Guoping |
| author_sort | Colvin, Steven |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>Fragile X syndrome (FXS) is a leading monogenic cause of intellectual disability and autism spectrum disorders, spurring decades of intense research and a multitude of mouse models. So far, these models do not recapitulate the genetic underpinning of classical FXS—CGG repeat-induced methylation of the<jats:italic>Fmr1</jats:italic>locus—and their findings have failed to translate into the clinic. We sought to answer whether this disparity was because of low repeat length and generated a novel mouse line with 341 repeats,<jats:italic>Fmr1<jats:sup>hs341</jats:sup></jats:italic>, which is the largest allele in mice reported to date. This repeat length is significantly longer than the 200 repeats generally required for methylation of the repeat tract and promoter region in FXS patients, which leads to silencing of the<jats:italic>FMR1</jats:italic>gene. Bisulfite sequencing fails to detect the robust methylation expected of FXS in<jats:italic>Fmr1<jats:sup>hs341</jats:sup></jats:italic>mice. Quantitative real-time PCR and Western blotting results also do not resemble FXS and instead produce a biochemical profile consistent with the fragile X-associated premutation disorders. These findings suggest that repeat length is unlikely to be the core determinant preventing methylation in mice, and other organisms phylogenetically closer to humans may be required to effectively model FXS.</jats:p> |
| first_indexed | 2024-09-23T16:05:13Z |
| format | Article |
| id | mit-1721.1/148777 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:05:13Z |
| publishDate | 2023 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/1487772023-03-28T03:03:47Z 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model Colvin, Steven Lea, Nick Zhang, Qiangge Wienisch, Martin Kaiser, Tobias Aida, Tomomi Feng, Guoping Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences <jats:title>Abstract</jats:title><jats:p>Fragile X syndrome (FXS) is a leading monogenic cause of intellectual disability and autism spectrum disorders, spurring decades of intense research and a multitude of mouse models. So far, these models do not recapitulate the genetic underpinning of classical FXS—CGG repeat-induced methylation of the<jats:italic>Fmr1</jats:italic>locus—and their findings have failed to translate into the clinic. We sought to answer whether this disparity was because of low repeat length and generated a novel mouse line with 341 repeats,<jats:italic>Fmr1<jats:sup>hs341</jats:sup></jats:italic>, which is the largest allele in mice reported to date. This repeat length is significantly longer than the 200 repeats generally required for methylation of the repeat tract and promoter region in FXS patients, which leads to silencing of the<jats:italic>FMR1</jats:italic>gene. Bisulfite sequencing fails to detect the robust methylation expected of FXS in<jats:italic>Fmr1<jats:sup>hs341</jats:sup></jats:italic>mice. Quantitative real-time PCR and Western blotting results also do not resemble FXS and instead produce a biochemical profile consistent with the fragile X-associated premutation disorders. These findings suggest that repeat length is unlikely to be the core determinant preventing methylation in mice, and other organisms phylogenetically closer to humans may be required to effectively model FXS.</jats:p> 2023-03-27T14:02:28Z 2023-03-27T14:02:28Z 2022 2023-03-27T13:54:55Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/148777 Colvin, Steven, Lea, Nick, Zhang, Qiangge, Wienisch, Martin, Kaiser, Tobias et al. 2022. "341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model." eneuro, 9 (5). en 10.1523/ENEURO.0142-22.2022 eneuro Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Colvin, Steven Lea, Nick Zhang, Qiangge Wienisch, Martin Kaiser, Tobias Aida, Tomomi Feng, Guoping 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model |
| title | 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model |
| title_full | 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model |
| title_fullStr | 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model |
| title_full_unstemmed | 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model |
| title_short | 341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model |
| title_sort | 341 repeats is not enough for methylation in a new fragile x mouse model |
| url | https://hdl.handle.net/1721.1/148777 |
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