ArticleHuman molecular genetics2015
Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 70 citations in OpenAlex.
- From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies.Molecular diagnosis & therapy · 2026Review
- Optimized clonal isolation and immortalization of Rett syndrome patient fibroblasts for in vitro modeling of MECP2 mutations.Scientific reports · 2025Article
- Mutation of MeCP2 at T158M Leads to Distinct Molecular and Phenotypic Abnormalities in Male and Female Mice.Cells · 2025Article
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome.Nucleic acids research · 2025Article
- Alzheimer's disease risk gene CD2AP is a dose-sensitive determinant of synaptic structure and plasticity.Human molecular genetics · 2024Article
- MeCP2 gene therapy ameliorates disease phenotype in mouse model for Pitt Hopkins syndrome.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities.Journal of neurodevelopmental disorders · 2024Review
- Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study.Journal of neurodevelopmental disorders · 2023Article
- Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome.International journal of molecular sciences · 2023Article
- Rett Syndrome: A Tale of Altered Genetics, Synaptic Plasticity, and Neurodevelopmental Dynamics.Cureus · 2023Review
- State-of-the-art therapies for Rett syndrome.Developmental medicine and child neurology · 2023Review
- Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives.Frontiers in neuroscience · 2023Review
- Selective Xi reactivation and alternative methods to restore MECP2 function in Rett syndrome.Trends in genetics : TIG · 2022Review
- Exploration of group II metabotropic glutamate receptor modulation in mouse models of Rett syndrome and MECP2 Duplication syndrome.Neuropharmacology · 2022Article
- Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.Genes, brain, and behavior · 2022Article
- Profiling beneficial and potential adverse effects of MeCP2 overexpression in a hypomorphic Rett syndrome mouse model.Genes, brain, and behavior · 2022Article
- Gene therapy for Rett syndrome.Genes, brain, and behavior · 2022Article
- Rett Syndrome andNeuropsychiatric disease and treatment · 2022Review
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
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 (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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.