A partial loss of function allele of Methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome

Department of Molecular and Human Genetics, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 07/2008; 17(12):1718-27. DOI: 10.1093/hmg/ddn062
Source: PubMed

ABSTRACT Rett Syndrome, an X-linked dominant neurodevelopmental disorder characterized by regression of language and hand use, is primarily caused by mutations in methyl-CpG-binding protein 2 (MECP2). Loss of function mutations in MECP2 are also found in other neurodevelopmental disorders such as autism, Angelman-like syndrome and non-specific mental retardation. Furthermore, duplication of the MECP2 genomic region results in mental retardation with speech and social problems. The common features of human neurodevelopmental disorders caused by the loss or increase of MeCP2 function suggest that even modest alterations of MeCP2 protein levels result in neurodevelopmental problems. To determine whether a small reduction in MeCP2 level has phenotypic consequences, we characterized a conditional mouse allele of Mecp2 that expresses 50% of the wild-type level of MeCP2. Upon careful behavioral analysis, mice that harbor this allele display a spectrum of abnormalities such as learning and motor deficits, decreased anxiety, altered social behavior and nest building, decreased pain recognition and disrupted breathing patterns. These results indicate that precise control of MeCP2 is critical for normal behavior and predict that human neurodevelopmental disorders will result from a subtle reduction in MeCP2 expression.

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Available from: Hsiao-Tuan Chao, Sep 27, 2015
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    • "Following restraint stress, we found that serum corticosterone levels were comparable between WT and Mecp2 1/2 mice. This is similar to a hypomorphic Mecp2 mouse that had a trend toward higher corticosterone at baseline with normal increases after restraint (Fyffe et al., 2008; Samaco et al., 2008) but differs from the Mecp2 308/Y mouse (McGill et al., 2006; De Filippis et al., 2013) and heterozygous mutants described by Samaco et al. (2013). HPA axis dysregulation has been described in the Mecp2 308/Y mouse model, which over-expresses Crh, has normal levels of basal plasma corticosterone and displays abnormally increased corticosterone levels in response to restraint stress, but appears to have a functional negative feedback loop (McGill et al., 2006; De Filippis et al., 2013). "
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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 · 3.37 Impact Factor
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    • "Doubling the Mecp2 expression level in mice resulted in impaired social interaction (Samaco et al, 2012). Mecp2 deficiency, however, also led to abnormal social behavior such as deficits in nest building, altered social interaction and enhanced aggression (Shahbazian et al, 2002; Moretti et al, 2005; Fyffe et al, 2008; Kerr et al, 2008; Samaco et al, 2008, 2009; Chao et al, 2010; Pearson et al, 2012). "
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    ABSTRACT: The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.
    EMBO Molecular Medicine 03/2014; DOI:10.1002/emmm.201303744 · 8.67 Impact Factor
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    • "This prediction is useful even if it is employed in the presymptomatic stages. In this case the mutation is a biomarker predicting a dyscognitive state (Chahrour & Zoghbi, 2007; Samaco et al., 2008). In AD, a biomarker detecting amyloid deposits would be a diagnostic tool for determination of dyscognitive state. "
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    ABSTRACT: Many symptoms of neurologic or psychiatric illness-such as cognitive impairment, depression, anxiety, attention deficits, and migraine-occur more frequently in people with epilepsy than in the general population. These diverse comorbidities present an underappreciated problem for people with epilepsy and their caregivers because they decrease quality of life, complicate treatment, and increase mortality. In fact, it has been suggested that comorbidities can have a greater effect on quality of life in people with epilepsy than the seizures themselves. There is increasing recognition of the frequency and impact of cognitive and behavioral comorbidities of epilepsy, highlighted in the 2012 Institute of Medicine report on epilepsy. Comorbidities have also been acknowledged, as a National Institutes of Health (NIH) Benchmark area for research in epilepsy. However, relatively little progress has been made in developing new therapies directed specifically at comorbidities. On the other hand, there have been many advances in understanding underlying mechanisms. These advances have made it possible to identify novel targets for therapy and prevention. As part of the International League Against Epilepsy/American Epilepsy Society workshop on preclinical therapy development for epilepsy, our working group considered the current state of understanding related to terminology, models, and strategies for therapy development for the comorbidities of epilepsy. Herein we summarize our findings and suggest ways to accelerate development of new therapies. We also consider important issues to improve research including those related to methodology, nonpharmacologic therapies, biomarkers, and infrastructure.
    Epilepsia 08/2013; 54 Suppl 4(Suppl 4):44-60. DOI:10.1111/epi.12298 · 4.57 Impact Factor
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