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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 ( Mecp2  R255X ). 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  Mecp2  R255X  mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of  MECP2  transgene  Mecp2  R255X  allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of  Mecp2.  Finally, we treated  Mecp2  R255X  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.

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