Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene
| Autor: | Jeffrey L. Neul, Shelly A. Buffington, Mauro Costa-Mattioli, Jonathan K. Merritt, Amanda R. Fisher, José A. Herrera, Meagan R. Pitcher, N. Carolyn Schanen, Mikhail Y. Kochukov |
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| Rok vydání: | 2015 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Methyl-CpG-Binding Protein 2 Transgene media_common.quotation_subject Nonsense Mutant Nonsense mutation Gene Expression Mice Transgenic Rett syndrome Mechanistic Target of Rapamycin Complex 1 Biology MECP2 Mice mental disorders Rett Syndrome Genetics medicine Animals RNA Messenger Transgenes Allele Molecular Biology Alleles Genetic Association Studies Genetics (clinical) media_common Behavior Animal TOR Serine-Threonine Kinases Articles General Medicine Fibroblasts medicine.disease Molecular biology Stop codon nervous system diseases Disease Models Animal Phenotype Amino Acid Substitution Multiprotein Complexes Mutation Gentamicins Signal Transduction |
| Zdroj: | Human Molecular Genetics. 24:2662-2672 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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