Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).
Bienvenu, T. & Chelly, J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nat. Rev. Genet. 7, 415–426 (2006).
Chahrour, M. & Zoghbi, H.Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).
Chen, R.Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327–331 (2001).
Guy, J., Hendrich, B., Holmes, M., Martin, J.E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001).
Shahbazian, M. et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35, 243–254 (2002).
Collins, A.L. et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13, 2679–2689 (2004).
Pelka, G.J. Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. Brain 129, 887–898 (2006).
Kerr, B., Alvarez-Saavedra, M., Sáez, M.A., Saona, A. & Young, J.I. Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice. Hum. Mol. Genet. 17, 1707–1717 (2008).
Samaco, R.C. et al. A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17, 1718–1727 (2008).
Jentarra, G.M. et al. Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation. BMC Neurosci. 11, 19 (2010).
Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007).
Lioy, D.T. et al. A role for glia in the progression of Rett's syndrome. Nature 475, 497–500 (2011).
Ho, K.L. et al. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol. Cell 29, 525–531 (2008).
Dani, V.S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA 102, 12560–12565 (2005).
Dani, V.S. & Nelson, S.B. Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome. J. Neurosci. 29, 11263–11270 (2009).
Wood, L., Gray, N.W., Zhou, Z., Greenberg, M.E. & Shepherd, G.M.G. Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in an RNA interference model of methyl-CpG-binding protein 2 deficiency. J. Neurosci. 29, 12440–12448 (2009).
Uhlhaas, P.J. & Singer, W. Abnormal neural oscillations and synchrony in schizophrenia. Nat. Rev. Neurosci. 11, 100–113 (2010).
Gandal, M.J., Edgar, J.C., Klook, K. & Siegel, S.J. Gamma synchrony: towards a translational biomarker for the treatment-resistant symptoms of schizophrenia. Neuropharmacology (2011).
Roberts, T.P.L. et al. MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism. Autism Res. 3, 8–18 (2010).
Gandal, M.J. et al. Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol. Psychiatry 68, 1100–1106 (2010).
Chao, H.-T. et al. Dysfunction in GABA signaling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010).
D'Cruz, J.A. et al. Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice. Neurobiol. Dis. 38, 8–16 (2010).
Bader, G.G., Witt-Engerström, I. & Hagberg, B. Neurophysiological findings in the Rett syndrome. II. Visual and auditory brainstem, middle and late evoked responses. Brain Dev. 11, 110–114 (1989).
Stauder, J.E.A., Smeets, E.E.J., van Mil, S.G.M. & Curfs, L.G.M. The development of visual- and auditory processing in Rett syndrome: an ERP study. Brain Dev. 28, 487–494 (2006).
Vacca, M. et al. MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region. Brain Dev. 23 Suppl 1: S246–S250 (2001).
Schanen, C. et al. Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am. J. Med. Genet. A. 126A, 129–140 (2004).
Armstrong, D.D. Neuropathology of Rett syndrome. J. Child Neurol. 20, 747–753 (2005).
Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).
Shahbazian, M.D., Antalffy, B., Armstrong, D.L. & Zoghbi, H.Y. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum. Mol. Genet. 11, 115–124 (2002).
Skene, P.J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).
Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).
Nan, X., Tate, P., Li, E. & Bird, A. DNA methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421 (1996).
Nuber, U.A. et al. Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum. Mol. Genet. 14, 2247–2256 (2005).
Jones, P.L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187–191 (1998).
Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).
Uhlhaas, P.J., Pipa, G., Neuenschwander, S., Wibral, M. & Singer, W. A new look at gamma? High- (>60 Hz) γ-band activity in cortical networks: function, mechanisms and impairment. Prog. Biophys. Mol. Biol. 105, 14–28 (2011).
Tallon-Baudry, C. & Bertrand, O. Oscillatory gamma activity in humans and its role in object representation. Trends Cogn. Sci. 3, 151–162 (1999).
Buzsáki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).
Winterer, G. et al. Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing. Clin. Neurophysiol. 111, 837–849 (2000).
Foster, B.A., Coffey, H.A., Morin, M.J. & Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science 286, 2507–2510 (1999).
Kishi, N. & Macklis, J.D. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol. Cell. Neurosci. 27, 306–321 (2004).
Uhlhaas, P.J. & Singer, W. Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 52, 155–168 (2006).
Ben-Ari, Y. Developing networks play a similar melody. Trends Neurosci. 24, 353–360 (2001).
Goffin, D. et al. Dopamine-dependent tuning of striatal inhibitory synaptogenesis. J. Neurosci. 30, 2935–2950 (2010).
Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).
Liao, W.-L. et al. Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc. Natl. Acad. Sci. USA 105, 6765–6770 (2008).
Canolty, R.T. et al. High gamma power is phase-locked to theta oscillations in human neocortex. Science 313, 1626–1628 (2006).
Hardisty-Hughes, R.E., Parker, A. & Brown, S.D.M. A hearing and vestibular phenotyping pipeline to identify mouse mutants with hearing impairment. Nat. Protoc. 5, 177–190 (2010).
Acknowledgements
This work is dedicated to the memory of Dr. Tom Kadesch, an inspirational colleague and mentor. We thank A. West, D. Epstein and members of the Zhou laboratory for critical readings of the manuscript, and the Intellectual and Developmental Disability Research Center Gene Manipulation Core (P30 HD18655) at the Children's Hospital Boston for generation of knockin mice (M. Thompson, Y. Zhou and H. Ye). This work was supported by grants from the US National Institutes of Health (R00 NS058391 and P30 HD026979), the Philadelphia Foundation and International Rett Syndrome Foundation to Z.Z. D.G. acknowledges the generous support of the Alavi-Dabiri Postdoctoral Fellowship. Z.Z. is a Pew Scholar in Biomedical Science.
Author information
Authors and Affiliations
Contributions
D.G. designed and performed the EEG and ERP studies, analyzed protein stability, and was involved in most aspects of the project, except for the generation of the mice. M. Allen and I.-T.J.W. characterized mouse phenotypes. L.Z. analyzed protein expression and interaction. M. Amorim analyzed DNA binding and gene expression. A.-R.S.R. and C.O. provided technical assistance. S.C. assisted with targeting construct. L.H. assisted with the generation of T158 antibody. A.M.-B. and J.A.B. helped design and interpret behavioral tests. G.C.C. and S.J.S. helped design and interpret the EEG and ERP studies. Z.Z. generated the knockin mice with supervision from M.E.G., designed the experiments and supervised the project. D.G. and Z.Z. wrote the paper.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–15 (PDF 5838 kb)
Supplementary Video 1
Motor deficits in Mecp2T158A/y mice. Example video shows locomotor deficits in male Mecp2+/y (starts at bottom left), Mecp2T158A/y (starts at top right) and Mecp2–/y mice (starts at top left) at 11 weeks of age. Both Mecp2T158A/y and Mecp2–/y mice show decreased locomotor activity and aberrant gait with splaying of hind limbs upon movement. (MOV 11659 kb)
Rights and permissions
About this article
Cite this article
Goffin, D., Allen, M., Zhang, L. et al. Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci 15, 274–283 (2012). https://doi.org/10.1038/nn.2997
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2997
This article is cited by
-
Effect of presentation rate on auditory processing in Rett syndrome: event-related potential study
Molecular Autism (2023)
-
Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome
Orphanet Journal of Rare Diseases (2022)
-
Auditory processing in rodent models of autism: a systematic review
Journal of Neurodevelopmental Disorders (2022)
-
Prenatal stress effects on offspring brain and behavior: Mediators, alterations and dysregulated epigenetic mechanisms
Journal of Biosciences (2021)
-
Deficits in skilled motor and auditory learning in a rat model of Rett syndrome
Journal of Neurodevelopmental Disorders (2020)