Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses
Open accessAbstract
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.
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Loss of MeCp2 results in reduced brain weight and thinning of the neocortex in some mouse models.
“Loss of MeCp2 results in reduced brain weight [67, 126], with thinning of the neocortex described in some mouse models [115, 200, 302].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [126]
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- Authors
- Goffin, D., Allen, M., Zhang, L., Amorim, M., Wang, I.-T. J., Reyes, A.-R. S., Mercado-Berton, A., Ong, C., Cohen, S., Hu, L., Blendy, J. A., Carlson, G. C., Siegel, S. J., Greenberg, M. E., & Zhou, Z.
- Affiliations
- University of Pennsylvania (US)
- Harvard University (US)
- Corresponding author
- Zhou, Zhaolan
- Venue
- Nature Neuroscience
- Published
- 2011-11-27
- Volume
- 15
- Issue
- 2
- Pages
- 274-283
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3267879
- OpenAlex
- W2086532160
- Cited by
- 226
- References
- 51
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 12 · 2023: 7 · 2022: 15 · 2021: 13 · 2020: 18 · 2019: 15 · 2018: 14 · 2017: 21 · 2016: 18 · 2015: 20 · 2014: 20 · 2013: 20 · 2012: 21
- FWCI
- 12.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH091850)
- National Institute of General Medical Sciences (T32GM007753, T32GM008076)
- National Institute of Neurological Disorders and Stroke (R00NS058391)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD026979, P30HD018655)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Rett syndrome, MeCP2, knock-in mice, protein stability, event-related potentials, motor impairment, learning and memory impairment, developmental regression, biomarkers, neural circuits
- MeSH terms
- Acoustic Stimulation, Age Factors, Alanine, Animals, Cells, Cultured, Cerebral Cortex, Conditioning, Psychological, DNA Mutational Analysis, DNA-Binding Proteins, Electroencephalography, Embryo, Mammalian, Exploratory Behavior, Fear, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Mutation, Neurons, Spectrum Analysis, Threonine, Evoked Potentials, Auditory, Brain Stem, Maze Learning, Chromatin Immunoprecipitation, Mice, Methyl-CpG-Binding Protein 2
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