PT  - JOURNAL ARTICLE
AU  - Steven Colvin
AU  - Nick Lea
AU  - Qiangge Zhang
AU  - Martin Wienisch
AU  - Tobias Kaiser
AU  - Tomomi Aida
AU  - Guoping Feng
TI  - 341 Repeats Is Not Enough for Methylation in a New Fragile X Mouse Model
AID  - 10.1523/ENEURO.0142-22.2022
DP  - 2022 Sep 01
TA  - eneuro
PG  - ENEURO.0142-22.2022
VI  - 9
IP  - 5
4099  - http://www.eneuro.org/content/9/5/ENEURO.0142-22.2022.short
4100  - http://www.eneuro.org/content/9/5/ENEURO.0142-22.2022.full
SO  - eNeuro2022 Sep 01; 9
AB  - 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 Fmr1 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, 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 the FMR1 gene. Bisulfite sequencing fails to detect the robust methylation expected of FXS in Fmr1hs341 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.