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Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome–like phenotypes

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  • Janine Lamonica
  • Deborah Kwon
  • Darren Lee Goffin
  • Polina Fenik
  • Brian S Johnson
  • Yue Cui
  • Hengy Guo
  • Sigrid Veasey
  • Zhaolan Zhou


Publication details

Journal Journal of Clinical Investigation
DateAccepted/In press - 9 Feb 2017
DateE-pub ahead of print - 10 Apr 2017
DatePublished (current) - 1 May 2017
Issue number5
Number of pages16
Pages (from-to)1889-1904
Early online date10/04/17
Original languageEnglish


Mutations in the X-linked gene encoding methyl-CpG–binding protein 2 (MeCP2) cause Rett syndrome (RTT), a neurological disorder affecting cognitive development, respiration, and motor function. Genetic restoration of MeCP2 expression reverses RTT-like phenotypes in mice, highlighting the need to search for therapeutic approaches. Here, we have developed knockin mice recapitulating the most common RTT-associated missense mutation, MeCP2 T158M. We found that the T158M mutation impaired MECP2 binding to methylated DNA and destabilized MeCP2 protein in an age-dependent manner, leading to the development of RTT-like phenotypes in these mice. Genetic elevation of MeCP2 T158M expression ameliorated multiple RTT-like features, including motor dysfunction and breathing irregularities, in both male and female mice. These improvements were accompanied by increased binding of MeCP2 T158M to DNA. Further, we found that the ubiquitin/proteasome pathway was responsible for MeCP2 T158M degradation and that proteasome inhibition increased MeCP2 T158M levels. Together, these findings demonstrate that increasing MeCP2 T158M protein expression is sufficient to mitigate RTT-like phenotypes and support the targeting of MeCP2 T158M expression or stability as an alternative therapeutic approach.

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© 2017 American Society for Clinical Investigation. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

    Research areas

  • Amino Acid Substitution, Animals, Gene Expression Regulation, Humans, Methyl-CpG-Binding Protein 2/biosynthesis, Mice, Mice, Transgenic, Mutation, Missense, Proteasome Endopeptidase Complex/genetics, Proteolysis, Rett Syndrome/genetics, Ubiquitin/genetics

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