title: Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation.
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.
authors.affiliation: Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, One Shields Ave, University of California, Davis, CA 95616, USA.
authors.forename: Raman P
authors.initials: RP
authors.lastname: Nagarajan
authors.forename: Amber R
authors.initials: AR
authors.lastname: Hogart
authors.forename: Ynnez
authors.initials: Y
authors.lastname: Gwye
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Martin
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001321:Autistic Disorder / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D046888:Tissue Array Analysis
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2