Reduced MeCP2 Expression is Frequent in Autism Frontal Cortex and Correlates with Aberrant MECP2 Promoter Methylation

Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, Davis, California 95616 , USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 10/2006; 1(4):e1-11. DOI: 10.4161/epi.1.4.3514
Source: PubMed


Mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2), cause most cases of Rett syndrome (RTT), an X-linked neurodevelopmental disorder. Both RTT and autism are "pervasive developmental disorders" and share a loss of social, cognitive and language skills and a gain in repetitive stereotyped behavior, following apparently normal perinatal development. Although MECP2 coding mutations are a rare cause of autism, MeCP2 expression defects were previously found in autism brain. To further study the role of MeCP2 in autism spectrum disorders (ASDs), we determined the frequency of MeCP2 expression defects in brain samples from autism and other ASDs. We also tested the hypotheses that MECP2 promoter mutations or aberrant promoter methylation correlate with reduced expression in cases of idiopathic autism. MeCP2 immunofluorescence in autism and other neurodevelopmental disorders was quantified by laser scanning cytometry and compared with control postmortem cerebral cortex samples on a large tissue microarray. A significant reduction in MeCP2 expression compared to age-matched controls was found in 11/14 autism (79%), 9/9 RTT (100%), 4/4 Angelman syndrome (100%), 3/4 Prader-Willi syndrome (75%), 3/5 Down syndrome (60%), and 2/2 attention deficit hyperactivity disorder (100%) frontal cortex samples. One autism female was heterozygous for a rare MECP2 promoter variant that correlated with reduced MeCP2 expression. A more frequent occurrence was significantly increased MECP2 promoter methylation in autism male frontal cortex compared to controls. Furthermore, percent promoter methylation of MECP2 significantly correlated with reduced MeCP2 protein expression. These results suggest that both genetic and epigenetic defects lead to reduced MeCP2 expression and may be important in the complex etiology of autism.

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    • "Other studies have also found such associations in ASD related loci. These include FMR1 (associated with Fragile X syndrome) and MECP2 (associated with Rett Syndrome, psychiatric disorders) (Grafodatskaya et al., 2010; Nagarajan et al., 2006). Junaid et al. (2011) found that high FA supplementation led aberrant expression of FMR1 in an animal model. "
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    ABSTRACT: Epigenetic mechanisms are now recognized to play roles in disease etiology. Several diseases increasing in frequency are associated with altered DNA methylation. DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Increased intake of these compounds correlates with decreased neural tube defects, although this mechanism is not well understood. Consumption of these methyl donor pathway components has increased in recent years due to fortification of grains and high supplemental levels of these compounds (e.g. vitamins, energy drinks). Additionally, people with mutations in one of the enzymes that assists in the methyl donor pathway (5-MTHFR) are directed to consume higher amounts of methyl donors to compensate. Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects. Individualized medicine may be necessary to determine the appropriate amounts of methyl donors to be consumed, particularly in women of child bearing age. Copyright © 2015. Published by Elsevier Ltd.
    Progress in Biophysics and Molecular Biology 04/2015; 118(1-2). DOI:10.1016/j.pbiomolbio.2015.03.007 · 2.27 Impact Factor
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    • "Mecp2 recognizes methylated DNA in gene promoter regions and recruits transcriptional modulators such as histone deacetylases that alter chromatin packaging [15]. Not only does MECP2 mutation underlie most cases of Rett syndrome [16] [17], the gene and its locus are implicated in non-syndromic autism [18] [19] [20] [21] and other psychiatric disorders [22,23]. Rett syndrome (ICD-10-CM: F84.2) is an Xlinked neurodevelopmental disorder identified almost exclusively in females due to lethality in males lacking a second X chromosome. "
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    ABSTRACT: Rett syndrome is a Pervasive Developmental Disorder (PDD) associated with de novo mutations of the methyl CpG-binding protein 2 (MECP2) gene. Mecp2 functions as a transcription factor that regulating the expression of hundreds of genes. Identification of the role of Mecp2 in specific neurodevelopmental symptoms remains an important research aim. We previously demonstrated that male mice possessing a truncation mutation in Mecp2 are hyper-social. We predicted that reduced fear or anxiety might underlie this enhanced affiliation. In order to probe risk assessment and anxiety-like behavior, we compared Mecp2 truncation mutants to their wild-type littermates in the elevated plus maze and elevated zero maze. Additionally, subjects were administered the mouse defense test battery to evaluate unconditioned fear- and panic-like behavior to a graded set of threat scenarios and a predator stimulus. Mutant mice showed no significant changes in anxiety-like behavior. Yet, they displayed hyper-reactive escape and defensive behaviors to an animate predatory threat stimulus. Notably, mutant mice engaged in exaggerated active defense responding to threat stimuli at nearly all phases of the fear battery. These results reveal abnormalities in emotion regulation in Mecp2 mutants particularly in response to ecologically relevant threats. This hyper-responsivity suggests that transcriptional targets of Mecp2 are critical to emotion regulation. Moreover, we suggest that detailed analysis of defensive behavior and aggression with ethologically relevant tasks provides an avenue to interrogate gene-behavior mechanisms neurodevelopmental and other psychiatric conditions. Copyright © 2015. Published by Elsevier Inc.
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    • "MeCP2 has been shown to be the major protein which binds to both 5mC and 5hmC in the brain (Mellen et al., 2012). MECP2 promoter hypermethylation is associated with MECP2 downregulation in the autistic brain (Nagarajan et al., 2006). Increased Mecp2 promoter methylation is also associated with reduced Mecp2 expression in postnatal mouse brain in response to maternal separation and stress (Franklin et al., 2010). "

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