A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome
Abstract
Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.
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Mecp2−/y mice of the Bird strain have a slightly shorter lifespan than those of the Jaenisch line.
“This agrees closely with the findings of Guy and her colleagues (Guy et al., 2001), and thereby confirms that Mecp2−/y mice of the Bird strain have a slightly shorter lifespan than those of the Jaenisch line (Chang et al., 2006).”
From Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis (2017) · cites this paper as Guy et al., 2001
The phenotype description accompanying Fig. 2 reports that Mecp2-null mice died at approximately 54 days, supporting the Bird-line lifespan part of the claim. It does not compare their lifespan with the Jaenisch line or establish that the difference is slight. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHeterozygous female mice on all genetic backgrounds, as well as female rats, become significantly overweight as they age.
“Interestingly, heterozygous female mice on all genetic backgrounds, as well as female rats, become significantly overweight as they age [115,117,125], although humans with RTT have a wide range in body mass index [15].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [117]
The body-weight discussion and Fig. 3 (p. 324) report that surviving Mecp2-null males on a C57BL/6×129 background became heavier than littermates. They do not establish weight gain in heterozygous females: the paper says weight effects depend on genetic background and reports underweight mutant mice on a C57BL/6 background. This mouse study provides no evidence about female rats. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMecp2 null males are normal at birth and weaning, but develop limb clasping, tremors, lethargy and abnormal breathing, symptoms that progressively worsen until death at 6-16 weeks of age.
“Null males are normal at birth and weaning, but develop limb clasping, tremors, lethargy and abnormal breathing, symptoms that progressively worsen until death at 6 – 16 weeks of age.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [3]
The phenotype description reports no initial symptoms, followed by hindlimb clasping, irregular breathing, reduced movement and deterioration ending in death at approximately 54 days. It does not report tremors or establish a 6–16-week age-at-death range. Figure 3a (p. 324) also shows that Mecp2-null males were significantly smaller than wild-type littermates from around weaning, qualifying the claim that they were normal at weaning. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBody weight in Mecp2 null mice differs depending on genetic background.
“Curiously, body weight in Mecp2 null mice differs depending on genetic background; male Mecp2tm1.1Bird/Y mice on a C57BL/6J background are substantially underweight by four weeks of age compared with wild-type littermates.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [117]
Mouse models recapitulate many of the symptoms of RTT.
“Mouse models recapitulate many of the symptoms of RTT and their study has provided insight into the physiological basis of disease3–5.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [3]
Male Mecp2/Y mice have a fully penetrant phenotype.
“Although female Mecp2/+ mice show phenotypic variance in part due to random X-chromosome inactivation, male Mecp2/Y mice have a fully penetrant phenotype.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [3]
Two alleles of Mecp2 are primarily used as mouse models of RTT: Mecp2tm1.1Bird, a null mutation, and Mecp2tm1.1Jae, which expresses low levels of a truncated protein.
“Two alleles of Mecp2 are primarily used as mouse models of RTT: Mecp2tm1.1Bird, a null mutation3, and Mecp2tm1.1Jae, which expresses low levels of a truncated protein32.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [3]
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Panayotis, N., Pratte, M., Borges-Correia, A., Ghata, A., Villard, L., & Roux, J.-C. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.006 · Cited by 54 · see citing works
Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4
Gomez, A. M., Froemke, R. C., & Burden, S. J. (2014) · eLife · doi:10.7554/elife.04287 · Cited by 47 · see citing works
Role of MeCP2, DNA methylation, and HDACs in regulating synapse function
Kavalali, E. T., Nelson, E. D., & Monteggia, L. M. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-011-9078-3 · Cited by 46 · see citing works
MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors
Mahgoub, M., Adachi, M., Suzuki, K., Liu, X., Kavalali, E. T., Chahrour, M. H., & Monteggia, L. M. (2016) · Nature Neuroscience · doi:10.1038/nn.4395 · Cited by 40 · see citing works
Biogenic amines and their metabolites are differentially affected in the Mecp2-deficient mouse brain
Panayotis, N., Ghata, A., Villard, L., & Roux, J.-C. (2011) · BMC Neuroscience · doi:10.1186/1471-2202-12-47 · Cited by 37 · see citing works
Janc, O. A., Hüser, M. A., Dietrich, K., Kempkes, B., Menzfeld, C., Hülsmann, S., & Müller, M. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00266 · Cited by 35 · see citing works
Genetics of Autism Spectrum Disorders
Rutter, M., & Thapar, A. (2014) · Handbook of Autism and Pervasive Developmental Disorders, Fourth Edition · doi:10.1002/9781118911389.hautc17 · Cited by 31 · see citing works
Lang, M., Wither, R. G., Brotchie, J. M., Wu, C., Zhang, L., & Eubanks, J. H. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds433 · Cited by 30 · see citing works
Stem cells and modeling of autism spectrum disorders
Freitas, B. C. G., Trujillo, C. A., Carromeu, C., Yusupova, M., Herai, R. H., & Muotri, A. R. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2012.09.017 · Cited by 27 · see citing works
Lopez, A. M., Chuang, J.-C., Posey, K. S., & Turley, S. D. (2017) · Brain Research · doi:10.1016/j.brainres.2016.10.021 · Cited by 24 · see citing works
The NuRD complex in neurodevelopment and disease: a case of sliding doors
Boulasiki, P., Tan, X. W., Spinelli, M., & Riccio, A. (2023) · Cells · doi:10.3390/cells12081179 · Cited by 22 · see citing works
Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice
Villani, C., Sacchetti, G., Bagnati, R., Passoni, A., Fusco, F., Carli, M., & Invernizzi, R. W. (2016) · eLife · doi:10.7554/elife.22409 · Cited by 20 · see citing works
Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway
Frasca, A., Miramondi, F., Butti, E., Indrigo, M., Balbontin Arenas, M., Postogna, F. M., Piffer, A., Bedogni, F., Pizzamiglio, L., Cambria, C., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00144-9 · Cited by 9 · see citing works
Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome
Audouard, E., Khefif, N., Gillet-Legrand, B., Nobilleau, F., Bouazizi, O., Stanga, S., Despres, G., Alves, S., Lamazière, A., Cartier, N., et al. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16060756 · Cited by 7 · see citing works
- Authors
- Guy, J., Hendrich, B., Holmes, M., Martin, J. E., & Bird, A.
- Affiliations
- Wellcome Centre for Cell Biology (GB)
- Western General Hospital (GB)
- Queen Mary University of London (GB)
- Corresponding author
- Bird, Adrian
- Venue
- Nature Genetics
- Published
- 2001-03
- Volume
- 27
- Issue
- 3
- Pages
- 322-326
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2127311839
- Cited by
- 1,558
- References
- 1
- Citations by year
- 2026: 47 · 2025: 55 · 2024: 39 · 2023: 38 · 2022: 53 · 2021: 65 · 2020: 67 · 2019: 58 · 2018: 60 · 2017: 72 · 2016: 92 · 2015: 81 · 2014: 77 · 2013: 75 · 2012: 94
- FWCI
- 29.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- ERA (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Rett syndrome, MeCP2, Mecp2-null mice, X-linked neurodevelopmental disorder, DNA methylation, gene silencing, neurological symptoms, Cre-loxP conditional knockout, embryonic stem cells
- MeSH terms
- Animals, Base Sequence, Chromosomal Proteins, Non-Histone, Disease Models, Animal, DNA-Binding Proteins, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nervous System Diseases, Phenotype, Repressor Proteins, RNA, Messenger, Rett Syndrome, DNA Primers, Mice, Knockout, Gene Targeting, Mice, Methyl-CpG-Binding Protein 2
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