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Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome–like phenotypes
Janine M. Lamonica, … , Sigrid Veasey, Zhaolan Zhou
Janine M. Lamonica, … , Sigrid Veasey, Zhaolan Zhou
Published April 10, 2017
Citation Information: J Clin Invest. 2017;127(5):1889-1904. https://doi.org/10.1172/JCI90967.
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Research Article Genetics Neuroscience

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

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Abstract

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.

Authors

Janine M. Lamonica, Deborah Y. Kwon, Darren Goffin, Polina Fenik, Brian S. Johnson, Yue Cui, Hengyi Guo, Sigrid Veasey, Zhaolan Zhou

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Figure 1

Mecp2T158M mice display RTT-like phenotypes.

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Mecp2T158M mice display RTT-like phenotypes.
(A) Body weights of Mecp2T...
(A) Body weights of Mecp2T158M/y male mice (n = 53, blue) were reduced relative to Mecp2+/y littermate body weights (n = 29, black) at 4 weeks and thereafter. ****P < 0.0001, by Student’s t test. (B) Mecp2T158M/y male mice had reduced brain weights at P42 and P100 (n = 8 for both genotypes and ages). **P < 0.01 and ****P < 0.0001, by Student’s t test with Bonferroni’s post-hoc test. (C) Age-dependent presentation of RTT-like phenotypes in Mecp2T158M/y (n = 45) versus Mecp2+/y (n = 24) male mice. ****P < 0.0001, by Student’s t test.(D) Kaplan-Meier survival curve revealed that Mecp2T158M/y male mice had premature lethality (Mecp2+/y median survival >200 days, n = 35, vs. Mecp2T158M/y median survival = 92 days, n = 39). (E) Body weight versus postnatal age for female Mecp2T158M/+ mice (n = 12) compared with Mecp2+/+ littermates (n = 10). Mecp2T158M/+ mice had significantly higher body weights at P250 or older. *P < 0.05, by Student’s t test. (F) Brain weights of female mice at P300 (n = 5 per genotype). **P < 0.01, by Student’s t test with Bonferroni’s post-hoc test. (G) Phenotypic scores of female Mecp2T158M/+ mice (n = 12) relative to scores for Mecp2+/+ littermates (n = 10). *P < 0.05, by Student’s t test. (H) Reduced survival of Mecp2T158M/+ (n = 76) compared with Mecp2+/+ (n = 14) female mice. Censored animals are indicated by a tick mark. All error bars represent the mean ± SEM.
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