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Background  Previous genetic studies demonstrated association between the transcription factor  ENGRAILED2  ( EN2 ) and Autism Spectrum Disorder (ASD). Subsequent molecular analysis determined that the  EN2  ASD-associated haplotype ( rs1861972 - rs1861973  A-C) functions as a transcriptional activator to increase gene expression.  EN2  is flanked by 5 genes,  SEROTONIN RECEPTOR5A (HTR5A), INSULIN INDUCED GENE1 (INSIG1) ,  CANOPY1 HOMOLOG (CNPY1), RNA BINDING MOTIF PROTEIN33 (RBM33) , and  SONIC HEDGEHOG (SHH) . These flanking genes are co-expressed with  EN2  during development and coordinate similar developmental processes. To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed.    Methods  qRT-PCR quantified mRNA levels for  EN2  and the 5 flanking genes in 78 post-mortem cerebellar samples. mRNA levels were correlated with both affection status and  rs1861972-rs1861973  genotype. Molecular analysis investigated whether  EN2  regulates flanking gene expression.    Results    EN2  levels are increased in affected A-C/G-T individuals (p = .0077). Affected individuals also display a significant increase in  SHH  and a decrease in  INSIG1  levels.  Rs1861972 - rs1861973  genotype is correlated with significant increases for  SHH  (A-C/G-T) and  CNPY1  (G-T/G-T) levels. Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with  EN2  and  SHH  being co-regulated, which provides a possible mechanism for increased  SHH  post-mortem levels.    Conclusions    EN2  levels are increased in affected individuals with an A-C/G-T genotype, supporting  EN2  as an ASD susceptibility gene.  SHH ,  CNPY1 , and  INSIG1  levels are also significantly altered depending upon affection status or  rs1861972 - rs1861973  genotype. Increased  EN2  levels likely contribute to elevated  SHH  expression observed in the post-mortem samples

Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum