Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis

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Ning , Z , Williams , J M , Kumari , R , Baranov , P & Moore , T 2019 , ' Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis ' , Frontiers in psychiatry , vol. 10 , 416 . https://doi.org/10.3389/fpsyt.2019.00416

Title: Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis
Author: Ning, Zhenfei; Williams, John M.; Kumari, Romika; Baranov, Pavel; Moore, Tom
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
Date: 2019-06-18
Language: eng
Number of pages: 16
Belongs to series: Frontiers in psychiatry
ISSN: 1664-0640
URI: http://hdl.handle.net/10138/311187
Abstract: Autism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebella 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 cerebella vermis lobules VI-VD 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 similar to 60 kb from SPRY3 acts as a silencer of Y-linked SPRY3 expression. Deletion of a beta-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.
Subject: autism
cerebellum
SPRY3
p75NTR
pseudoautosomal region
TMLHE
camitine
BETA-SATELLITE DNA
SPECTRUM DISORDER
NEUROTROPHIN RECEPTOR
GENE-EXPRESSION
PURKINJE-CELLS
DEATH RECEPTOR
BRAIN
RISK
CHILDREN
REVEALS
3124 Neurology and psychiatry
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