Abstract
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 SPRY3, which is adjacent to X chromosome-linked TMLHE, a known autism susceptibility gene. SPRY3 is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse Spry3 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 p75NTR, which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate SPRY3 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 SPRY3, which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ∼60 kb from SPRY3 acts as a silencer of Y-linked SPRY3 expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to trans-acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked SPRY3. This proposed male-specific mechanism could contribute to the male bias in autism prevalence.
Highlights
Autism is a spectrum disorder whose core features include language delay, social deficits, and restricted interests and repetitive behaviours
We examined the expression of SPRY3 and its functionally associated genes in cerebellum, and we analyzed genetic variation in predicted X and Y chromosome regulatory regions that may impact on SPRY3 expression
We propose that SPRY3 deregulation affects the functioning of the BDNF–TrkB– p75NTR neurotrophin pathway, leading to cerebellar Purkinje cell pathology
Summary
Autism is a spectrum disorder whose core features include language delay, social deficits, and restricted interests and repetitive behaviours. The ESSENCE protocol was developed in response to the increasing diagnosis of autism associated with an expanding list of co-morbidities, including cases in which the co-morbidity may be the predominant clinical entity [1, 4]. There is a trend towards the increased diagnosis and inclusion of cases at the mild end of the spectrum [5]. The combined effects of these trends may explain the current estimates of autism prevalence in school. Heritability estimates for autism are high, ranging from 38% [8] to more than 80% [9, 10], and there is an emerging consensus that the majority of the genetic risk is attributable to common genetic variants of small effect size acting in combination with rare or de novo variants of larger effect size [11,12,13,14,15]
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