title: Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene.
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.
authors: Interdepartmental Program in Translational Biology and Molecular Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: Meagan R
authors: MR
authors: Pitcher
authors: Interdepartmental Program in Translational Biology and Molecular Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: José A
authors: JA
authors: Herrera
authors: Department of Neuroscience, Memory and Brain Research Center and.
authors: Shelly A
authors: SA
authors: Buffington
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: Mikhail Y
authors: MY
authors: Kochukov
authors: Interdepartmental Program in Translational Biology and Molecular Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: Jonathan K
authors: JK
authors: Merritt
authors: Department of Biological Sciences, University of Delaware, Newark, DE, USA and.
authors: Amanda R
authors: AR
authors: Fisher
authors: Nemours/Al DuPont Hospital for Children, Wilmington, DE, USA.
authors: N Carolyn
authors: NC
authors: Schanen
authors: Department of Neuroscience, Memory and Brain Research Center and.
authors: Mauro
authors: M
authors: Costa-Mattioli
authors: Interdepartmental Program in Translational Biology and Molecular Medicine, Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA, jneul@bcm.edu jneul@ucsd.edu.
authors: Jeffrey L
authors: JL
authors: Neul
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D056726:Genetic Association Studies; D005839:Gentamicins / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019076:Transgenes
chemical_list: D005839:Gentamicins; D051783:Methyl-CpG-Binding Protein 2; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
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