An AT-Hook Domain in MeCP2 Determines the Clinical Course of Rett Syndrome and Related Disorders

Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
Cell (Impact Factor: 33.12). 02/2013; 152(5):984-96. DOI: 10.1016/j.cell.2013.01.038
Source: PubMed

ABSTRACT Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2's key functions is to alter chromatin structure.

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    • "Top: Comparison of hippocampus from Mecp2 1/y WT and male mice with a late truncating Mecp2 G273X mutation (Mecp2-G273X). See Baker et al. (2013) for details of mouse generation and phenotype; Middle: Comparison of amygdala from Mecp2 1/y and Mecp2 2/y mice. See Samaco et al. (2013); Bottom: Comparison of hypothalamus from Mecp2 1/y and Mecp2 2/y mice. "
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    ABSTRACT: Rett syndrome is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however behavioural and emotional symptoms also severely affect their quality of life. Here we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of Rett syndrome (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behaviour of the Mecp2(+/-) mice were found to be reversible with environmental enrichment from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of Rett syndrome is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating HPA-axis dysregulation. Environmental enrichment of Mecp2(+/-) mice normalised basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of Rett syndrome, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioural and cognitive dimensions, of this devastating neurodevelopmental disorder. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Developmental Neurobiology 05/2015; DOI:10.1002/dneu.22308 · 4.19 Impact Factor
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    • "Besides regulating transcription repression, SUMO is thought to be a modifier of chromatin structure and function (Cube~ nas-Potts and Matunis 2013). More and more recent studies showed that MeCP2 is involved in normal chromatin structure maintenance (Skene et al. 2010; Baker et al. 2013). Our SUMO assay data indicate that MeCP2 has multiple SUMOylated lysines and SUMOylation at other sites may contribute to alteration of chromatin state. "
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    ABSTRACT: Methyl CpG binding protein 2 (MeCP2) binds to methylated DNA and acts as a transcriptional repressor. Mutations of human MECP2 gene lead to Rett syndrome, a severe neural developmental disorder. Here we report that the MeCP2 protein can be modified by covalent linkage to small ubiquitin-like modifier (SUMO) and SUMOylation at lysine 223 is necessary for its transcriptional repression function. SUMOylation of MeCP2 is required for the recruitment of HDAC1/2 complex. Mutation of MeCP2 lysine 223 to arginine abolishes its suppression of gene expression in mouse primary cortical neurons. Significantly, mutation of MeCP2 K223 site leads to developmental deficiency of rat hippocampal synapses in vitro and in vivo. Thus, the SUMOylation of MeCP2 at K223 is a critical switch for transcriptional repression and plays a crucial function in regulating synaptic development in the central nervous system. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 11/2013; 128(6). DOI:10.1111/jnc.12523 · 4.24 Impact Factor
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    • "In summary, Baker et al. (2013) identified a novel AT-hook domain of MeCP2 that plays an important role in chromatin organization, providing a new model involving an additional protein partner, which, incidentally, is also implicated in a neurodevelopmental disorder associated with intellectual disability. They took advantage of the correlation between mouse models and human individuals, identified the pathogenesis of various RTT-like phenotypes in novel mouse lines, which increased our understanding of how different MeCP2 functions are affected by various disease-causing mutations. "
    Frontiers in Cellular Neuroscience 05/2013; 7:64. DOI:10.3389/fncel.2013.00064 · 4.18 Impact Factor
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