341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model
Author(s)
Colvin, Steven; Lea, Nick; Zhang, Qiangge; Wienisch, Martin; Kaiser, Tobias; Aida, Tomomi; Feng, Guoping; ... Show more Show less
DownloadPublished version (1.595Mb)
Publisher with Creative Commons License
Publisher with Creative Commons License
Creative Commons Attribution
Terms of use
Metadata
Show full item recordAbstract
<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>
Date issued
2022Department
Massachusetts Institute of Technology. Department of Brain and Cognitive SciencesJournal
eneuro
Publisher
Society for Neuroscience
Citation
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).
Version: Final published version