Opposite Expression Patterns of and in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis.

Autism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebellar abnormalities, including Purkinje cell deficits in the vermis, are consistently reported, and rodent models of cerebellar dysfunction exhibit features analogous to human autism. We previously analyzed the regulation and expression of the pseudoautosomal region 2 gene , which is adjacent to X chromosome-linked , a known autism susceptibility gene. is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse is not expressed in cerebellar vermis lobules VI-VII and X, regions which exhibit significant Purkinje cell loss or abnormalities in autism. However, these lobules have relatively high expression of , which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate expression in these lobules could interact with TrkB and p75NTR signaling pathways resulting in Purkinje cell pathology. We report preliminary characterization of X and Y chromosome-linked regulatory sequences upstream of , which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ∼60 kb from acts as a silencer of Y-linked expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to -acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked . This proposed male-specific mechanism could contribute to the male bias in autism prevalence.