Article

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

ABSTRACT

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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    • "regarding the pyrophosphatase/phosphodiesterase family members was retrieved from previous published articles on NPP-1, NPP-2, NPP-3 and NPP-4 (Goding et al., 2003), NPP-5 (Ohe et al., 2003), NPP-6 (Sakagami et al., 2005) and NPP-7 (Duan et al., 2003). reported to overlap with RTT and MECP2 duplication syndrome, and reduced MeCP2 levels have been evidenced in brains of ASD patients (Nagarajan et al., 2006). Although OS, UPR-ER stress and glycosylation changes appear to be general pathophysiological processes linked to RTT, NPP-5 and its glycosylation status appear to be specific targets, intimately linked to mechanisms involved in the disease pathogenesis. "
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    ABSTRACT: Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5.
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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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    • "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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