Overexpression of Methyl-CpG Binding Protein 2 Impairs TH1 Responses

Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
Science translational medicine (Impact Factor: 15.84). 12/2012; 4(163):163ra158. DOI: 10.1126/scitranslmed.3004430
Source: PubMed


The DNA binding protein methyl-CpG binding protein 2 (MeCP2) critically influences neuronal and brain function by modulating gene expression, and children with overexpression of the MECP2 gene exhibit postnatal neurological syndromes. We demonstrate that some children with MECP2 duplication also display variable immunological abnormalities that include reductions in memory T and B cells and natural killer cells and immunoglobulin assay responses. Moreover, whereas mice with MeCP2 overexpression were unable to control infection with the intra-macrophage parasite Leishmania major and secrete interferon-γ (IFN-γ) from involved lymph nodes, they were able to control airway fungal infection by Aspergillus niger and mount protective T helper cell type 2 (T(H)2)-dependent allergic responses. Relative to normal T cells, T(H) cells from children and mice with MECP2 duplication displayed similar impairments in IFN-γ secretion and T(H)1 responses that were due to both MeCP2-dependent suppression of IFN-γ transcription and sequestration of the IFN-γ locus as assessed by chromatin immunoprecipitation assay. Thus, overexpressed MeCP2 aberrantly suppresses IFN-γ secretion from T(H) cells, potentially leading to a partially immunodeficient state. Our findings establish a rational basis for identifying, treating, and preventing infectious complications potentially affecting children with MECP2 duplication.

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Available from: Luz Roberts, Oct 20, 2014
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    • "Interestingly, the phenotype of recurrent infections is not consistently manifested in all affected boys with Xq28 duplications that included IRAK1 (Van Esch, 2012). A recent study indicated that MECP2 duplication impairs INF-α secretion from T helper cells contributing to the susceptibility to infections in mice and humans (Yang et al., 2012). The genetic background and susceptibility factors and simultaneous duplications of other genes with MECP2 may modify phenotypes in the probands (Honda et al., 2012; Peters et al., 2013a; Sanmann et al., 2012). "
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    ABSTRACT: The aim of this study was to determine the frequency, timing, and associated features of developmental regression in MECP2 duplication syndrome. We also examined whether duplication size was associated with regression. Comprehensive psychological evaluations were used to assess 17 boys with MECP2 duplication syndrome. Information about regression was gathered via parent report. Eight of 17 boys exhibited regression in language skills, while seven of 17 exhibited regression in other skill areas. Regression in "other skill" areas coincided with seizure onset and with a prior autism diagnosis in six of seven participants. Regression was not associated with duplication size. Questions remain as to why some boys regress, and future work is necessary to understand the underlying mechanism(s) that causes regression.
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