Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene

Meagan R. Pitcher, José A. Herrera, Shelly Buffington, Mikhail Y. Kochukov, Jonathan K. Merritt, Amanda R. Fisher, N. Carolyn Schanen, Mauro Costa-Mattioli, Jeffrey L. Neul

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2R255X). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2R255X mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2R255X allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2R255X embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein.

Original languageEnglish (US)
Pages (from-to)2662-2672
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number9
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Methyl-CpG-Binding Protein 2
Rett Syndrome
Transgenes
Nonsense Codon
Phenotype
Alleles
Mutation
Mouse Mecp2 protein
Terminator Codon
Gentamicins
Pharmaceutical Preparations
Proteins
Fibroblasts
Guidelines

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Pitcher, M. R., Herrera, J. A., Buffington, S., Kochukov, M. Y., Merritt, J. K., Fisher, A. R., ... Neul, J. L. (2015). Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. Human Molecular Genetics, 24(9), 2662-2672. https://doi.org/10.1093/hmg/ddv030

Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. / Pitcher, Meagan R.; Herrera, José A.; Buffington, Shelly; Kochukov, Mikhail Y.; Merritt, Jonathan K.; Fisher, Amanda R.; Schanen, N. Carolyn; Costa-Mattioli, Mauro; Neul, Jeffrey L.

In: Human Molecular Genetics, Vol. 24, No. 9, 01.01.2015, p. 2662-2672.

Research output: Contribution to journalArticle

Pitcher, MR, Herrera, JA, Buffington, S, Kochukov, MY, Merritt, JK, Fisher, AR, Schanen, NC, Costa-Mattioli, M & Neul, JL 2015, 'Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene', Human Molecular Genetics, vol. 24, no. 9, pp. 2662-2672. https://doi.org/10.1093/hmg/ddv030
Pitcher, Meagan R. ; Herrera, José A. ; Buffington, Shelly ; Kochukov, Mikhail Y. ; Merritt, Jonathan K. ; Fisher, Amanda R. ; Schanen, N. Carolyn ; Costa-Mattioli, Mauro ; Neul, Jeffrey L. / Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 9. pp. 2662-2672.
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AU - Merritt, Jonathan K.

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AU - Schanen, N. Carolyn

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