Mild overexpression of MeCP2 causes a progressive neurological disorder in mice
Abstract
Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.
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Rett syndrome disease may be ameliorated or even reversed by genetic or pharmacological means after symptom onset.
“These findings suggest that the disease may be ameliorated or even reversed by genetic or pharmacological means after symptom onset2,7.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [7]
Supraphysiological expression of target proteins could be hazardous, as shown in Rett syndrome, GM2 gangliosidosis, and Spinal Muscular Atrophy.
“In fact, supraphysiological expression of target proteins could be hazardous, as previously shown in the context of Rett syndrome [83], GM2 gangliosidosis [84], and Spinal Muscular Atrophy [85].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [83]
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- Authors
- Collins, A. L., Levenson, J. M., Vilaythong, A. P., Richman, R., Armstrong, D. L., Noebels, J. L., David Sweatt, J., & Zoghbi, H. Y.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Collins, Ann L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-09-06
- Volume
- 13
- Issue
- 21
- Pages
- 2679-2689
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2155388782
- Cited by
- 626
- References
- 4
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 22 · 2023: 23 · 2022: 29 · 2021: 34 · 2020: 17 · 2019: 22 · 2018: 25 · 2017: 35 · 2016: 32 · 2015: 29 · 2014: 33 · 2013: 40 · 2012: 53
- FWCI
- 11.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (5f31mh065097-03)
- National Institute of Mental Health (MH 57014, MH65097-01, R01MH057014)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD40301, P30HD024064, P30 HD24064, P01HD040301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- MeCP2, Rett syndrome, transgenic mice, X-linked neurodevelopmental disorder, gain-of-function mutations, seizures, motor learning, contextual learning, synaptic plasticity, hippocampus, transcriptional repressor
- MeSH terms
- Animals, Behavior, Animal, Chromosomal Proteins, Non-Histone, Disease Models, Animal, DNA-Binding Proteins, Electroencephalography, Electrophysiology, Humans, Immunohistochemistry, Mice, Transgenic, Mutation, Nervous System Diseases, Repressor Proteins, Time Factors, X Chromosome, Blotting, Western, Rett Syndrome, Gene Expression Regulation, Developmental, Mice, Methyl-CpG-Binding Protein 2
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