Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action
Abstract
Rett syndrome (RTT) is a devastating genetic disorder that worldwide represents the most common genetic cause of severe intellectual disability in females. Most cases are caused by mutations in the X-linked MECP2 gene. Several recent studies have demonstrated that RTT mimicking animal models do not develop an irreversible condition and phenotypic rescue is possible. However, no cure for RTT has been identified so far, and patients are only given symptomatic and supportive treatments. The development of clinical applications imposes a more comprehensive knowledge of MeCP2 functional role(s) and their relevance for RTT pathobiology. Herein, we thoroughly survey the knowledge about MeCP2 structure and functions, highlighting the necessity of identifying more functional domains and the value of molecular genetics. Given that, in our opinion, RTT ultimately is generated by perturbations in gene transcription and so far no genes/pathways have been consistently linked to a dysfunctional MeCP2, we have used higher-level bioinformatic analyses to identify commonly deregulated mechanisms in MeCP2-defective samples. In this review we present our results and discuss the possible value of the utilized approach.
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Synaptic defects are a hallmark of RTT.
“Synaptic defects are a hallmark of RTT (Bedogni et al., 2014;Boggio et al., 2010;Calfa et al., 2015;Dani et al., 2005;Fukuda et al., 2005)”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Bedogni et al., 2014
Cites
MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription
Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., & Zoghbi, H. Y. (2008) · Science · doi:10.1126/science.1153252 · Cited by 1,823 · see citing works
Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice
Chen, R. Z., Akbarian, S., Tudor, M., & Jaenisch, R. (2001) · Nature Genetics · doi:10.1038/85906 · Cited by 1,275 · see citing works
Chromatin Compaction by Human MeCP2
Georgel, P. T., Horowitz-Scherer, R. A., Adkins, N., Woodcock, C. L., Wade, P. A., & Hansen, J. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305308200 · Cited by 305 · see citing works
Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons
Smrt, R. D., Eaves-Egenes, J., Barkho, B. Z., Santistevan, N. J., Zhao, C., Aimone, J. B., Gage, F. H., & Zhao, X. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.04.005 · Cited by 239 · see citing works
A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome
Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., et al. (2013) · Nature Genetics · doi:10.1038/ng.2714 · Cited by 234 · see citing works
Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR
Ebert, D. H., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., Navarro, A. J., Lyst, M. J., Ekiert, R., Bird, A. P., et al. (2013) · Nature · doi:10.1038/nature12348 · Cited by 227 · see citing works
Neuropathology of Rett syndrome
Armstrong, D. D. (2005) · Journal of Child Neurology · doi:10.1177/08830738050200082401 · Cited by 207 · see citing works
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MeCP2 related studies benefit from the use of CD1 as genetic background
Cobolli Gigli, C., Scaramuzza, L., Gandaglia, A., Bellini, E., Gabaglio, M., Parolaro, D., Kilstrup-Nielsen, C., Landsberger, N., & Bedogni, F. (2016) · PLOS ONE · doi:10.1371/journal.pone.0153473 · Cited by 37 · see citing works
Self-citationImpaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome
Postogna, F. M., Giancroce, N., Cabasino, C., Biella, F., Roggero, O. M., Breccia, M., Morelli, L., Colombo, D., Arcari, A., Lunghi, G., et al. (2026) · doi:10.64898/2026.07.29.741426 · Cited by 1 · see citing works
“Synaptic defects are a hallmark of RTT (Bedogni et al., 2014; Boggio et al., 2010; Calfa et al., 2015; Dani et al., 2005; Fukuda et al., 2005) and MECP2 mutant astrocytes contribute to neuronal alterations through non-cell-autonomous mechanisms (Albizzati et al., 2024; Ballas et al., 2009; Sun et…”
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- Authors
- Bedogni, F., Rossi, R. L., Galli, F., Cobolli Gigli, C., Gandaglia, A., Kilstrup-Nielsen, C., & Landsberger, N.
- Affiliations
- University of Insubria (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- IRCCS Ospedale San Raffaele (IT)
- Corresponding author
- Landsberger, Nicoletta
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 46
- Pages
- 187-201
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W1987829135
- Cited by
- 51
- References
- 9
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 3
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- Funders
- Fondazione Cariplo (2010-0724, FP7-PEOPLE-ITN-2008)
- Jerome Lejeune Foundation
- Fondazione Telethon (GGP10032)
- IRSF
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Rett syndrome, MeCP2, MECP2 mutations, X-linked intellectual disability, transcriptional regulation, phenotypic rescue
- MeSH terms
- Animals, Humans, Signal Transduction, Rett Syndrome, Gene Expression Regulation, Developmental, Computational Biology, Methyl-CpG-Binding Protein 2
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