title: Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses.
abstract: Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation.
authors: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Darren
authors: D
authors: Goffin
authors: Megan
authors: M
authors: Allen
authors: Le
authors: L
authors: Zhang
authors: Maria
authors: M
authors: Amorim
authors: I-Ting Judy
authors: IT
authors: Wang
authors: Arith-Ruth S
authors: AR
authors: Reyes
authors: Amy
authors: A
authors: Mercado-Berton
authors: Caroline
authors: C
authors: Ong
authors: Sonia
authors: S
authors: Cohen
authors: Linda
authors: L
authors: Hu
authors: Julie A
authors: JA
authors: Blendy
authors: Gregory C
authors: GC
authors: Carlson
authors: Steve J
authors: SJ
authors: Siegel
authors: Michael E
authors: ME
authors: Greenberg
authors: Zhaolan
authors: Z
authors: Zhou
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation; D003213:Conditioning, Psychological / Q000502:physiology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004569:Electroencephalography; D004622:Embryo, Mammalian; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D013057:Spectrum Analysis; D013912:Threonine / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D013912:Threonine; D000409:Alanine