title: Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects.
abstract: BACKGROUND
  Reelin plays a pivotal role in neurodevelopment and in post-natal synaptic plasticity and has been implicated in the pathogenesis of autism spectrum disorder (ASD). The reelin (RELN) gene expression is significantly decreased in ASD, both in the brain and peripherally. Methylation at the RELN gene promoter is largely triggered at puberty, and hypermethylation has been found in post-mortem brains of schizophrenic and bipolar patients.
  
  
  METHODS
  In this study, we assessed RELN gene methylation status in post-mortem temporocortical tissue samples (BA41/42 or 22) of six pairs of post-puberal individuals with ASD and typically developing subjects, matched for sex (male:female, M:F = 5:1), age, and post-mortem interval.
  
  
  RESULTS
  ASD patients display a significantly higher number of methylated CpG islands and heavier methylation in the 5' region of the RELN gene promoter, spanning from -458 to -223 bp, whereas controls have more methylated CpG positions and greater extent of methylation at the 3' promoter region, spanning from -222 to +1 bp. The most upstream promoter region (-458 to -364 bp) is methylated only in ASD brains, while the most downstream region (-131 to +1 bp) is methylated exclusively in control brains. Within this general framework, three different methylation patterns are discernible, each correlated with different extents of reduction in reelin gene expression among ASD individuals compared to controls.
  
  
  CONCLUSIONS
  The methylation pattern is different in ASD and control post-mortem brains. ASD-specific CpG positions, located in the most upstream gene promoter region, may exert a functional role potentially conferring ASD risk by blunting RELN gene expression.
authors.affiliation: Unit of Child and Adolescent Neuropsychiatry, University Campus Bio-Medico, Rome, Italy ; Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Lintas
authors.affiliation: Unit of Child and Adolescent Neuropsychiatry, University Campus Bio-Medico, Rome, Italy ; Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.affiliation: Unit of Child and Adolescent Neuropsychiatry, "Gaetano Martino" University Hospital, University of Messina, via Consolare Valeria 1, I-98125 Messina, Italy ; Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
keywords: Autism; DNA methylation; Epigenetics; Post-mortem brains; Reelin