341 Repeats is Not Enough for Methylation in a New Fragile X Mouse Model
Name
ENEURO.0142-22.2022.full.pdf
Description
Published version
Size
1.6 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Colvin, Steven
Lea, Nick
Zhang, Qiangge
Wienisch, Martin
Kaiser, Tobias
Aida, Tomomi
Feng, Guoping
Date Issued
2022
Journal
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
Abstract
AbstractFragile 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 theFmr1locus—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,Fmr1hs341, 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 theFMR1gene. Bisulfite sequencing fails to detect the robust methylation expected of FXS inFmr1hs341mice. 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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1523/ENEURO.0142-22.2022
