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      Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism

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          Abstract

          Background

          Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant impairment in reciprocal social interactions and communication coupled with stereotyped, repetitive behaviors and restricted interests. Although genomic and functional studies are beginning to reveal some of the genetic complexity and underlying pathobiology of ASD, the consistently reported male bias of ASD remains an enigma. We have recently proposed that retinoic acid-related orphan receptor alpha ( RORA), which is reduced in the brain and lymphoblastoid cell lines of multiple cohorts of individuals with ASD and oppositely regulated by male and female hormones, might contribute to the sex bias in autism by differentially regulating target genes, including CYP19A1 (aromatase), in a sex-dependent manner that can also lead to elevated testosterone levels, a proposed risk factor for autism.

          Methods

          In this study, we examine sex differences in RORA and aromatase protein levels in cortical tissues of unaffected and affected males and females by re-analyzing pre-existing confocal immunofluorescence data from our laboratory. We further investigated the expression of RORA and its correlation with several of its validated transcriptional targets in the orbital frontal cortex and cerebellum as a function of development using RNAseq data from the BrainSpan Atlas of the Developing Human Brain. In a pilot study, we also analyzed the expression of Rora and the same transcriptional targets in the cortex and cerebellum of adult wild-type male and female C57BL/6 mice.

          Results

          Our findings suggest that Rora/RORA and several of its transcriptional targets may exhibit sexually dimorphic expression in certain regions of the brain of both mice and humans. Interestingly, the correlation coefficients between Rora expression and that of its targets are much higher in the cortex of male mice relative to that of female mice. A strong positive correlation between the levels of RORA and aromatase proteins is also seen in the cortex of control human males and females as well as ASD males, but not ASD females.

          Conclusions

          Based on these studies, we suggest that disruption of Rora/ RORA expression may have a greater impact on males, since sex differences in the correlation of RORA and target gene expression indicate that RORA-deficient males may experience greater dysregulation of genes relevant to ASD in certain brain regions during development.

          Electronic supplementary material

          The online version of this article (doi:10.1186/2040-2392-6-7) contains supplementary material, which is available to authorized users.

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          Most cited references 86

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          Diagnostic and Statistical Manual of Mental Disorders

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            Diagnostic and statistical manual of mental disorders.

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              Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

              It is well established that autism spectrum disorders (ASD) have a strong genetic component. However, for at least 70% of cases, the underlying genetic cause is unknown 1 . Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes—so-called sporadic or simplex families 2,3 , we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported 4 . Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19) 4 , for a total of 677 individual exomes from 209 families. Here we show de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD 5 . Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes, CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3, and SCN1A. Combined with copy number variant (CNV) data, these results suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics.
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                Author and article information

                Contributors
                valhu@gwu.edu
                Tewarit.Sa@chula.ac.th
                rachel.sherrard@snv.jussieu.fr
                kocherk@gwu.edu
                Journal
                Mol Autism
                Mol Autism
                Molecular Autism
                BioMed Central (London )
                2040-2392
                13 May 2015
                13 May 2015
                2015
                : 6
                Affiliations
                [ ]Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye St. NW, Washington, DC 20037 USA
                [ ]Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
                [ ]Institut de Biologie Paris Seine, Sorbonne Universités, UPMC Univ Paris 06 & CNRS, UMR 8256 Biological Adaptation and Ageing, F-75005 Paris, France
                Article
                162
                10.1186/2040-2392-6-7
                4459681
                26056561
                © Hu et al.; licensee BioMed Central. 2015

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Research
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                © The Author(s) 2015

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