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Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses.

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.

Pubmed ID: 22119903


  • Goffin D
  • Allen M
  • Zhang L
  • Amorim M
  • Wang IT
  • Reyes AR
  • Mercado-Berton A
  • Ong C
  • Cohen S
  • Hu L
  • Blendy JA
  • Carlson GC
  • Siegel SJ
  • Greenberg ME
  • Zhou Z


Nature neuroscience

Publication Data

February 27, 2012

Associated Grants

  • Agency: NICHD NIH HHS, Id: P30 HD018655
  • Agency: NICHD NIH HHS, Id: P30 HD018655-27
  • Agency: NICHD NIH HHS, Id: P30 HD026979
  • Agency: NICHD NIH HHS, Id: P30 HD026979-20
  • Agency: NICHD NIH HHS, Id: P30 HD18655
  • Agency: NINDS NIH HHS, Id: R00 NS058391
  • Agency: NINDS NIH HHS, Id: R00 NS058391
  • Agency: NINDS NIH HHS, Id: R00 NS058391-05
  • Agency: NIMH NIH HHS, Id: R01 MH091850
  • Agency: NIGMS NIH HHS, Id: T32 GM007753

Mesh Terms

  • Acoustic Stimulation
  • Age Factors
  • Alanine
  • Animals
  • Cells, Cultured
  • Cerebral Cortex
  • Chromatin Immunoprecipitation
  • Conditioning (Psychology)
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Electroencephalography
  • Embryo, Mammalian
  • Evoked Potentials, Auditory, Brain Stem
  • Exploratory Behavior
  • Fear
  • Gene Expression Regulation
  • Humans
  • Maze Learning
  • Methyl-CpG-Binding Protein 2
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity
  • Mutation
  • Neurons
  • Spectrum Analysis
  • Threonine