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      αT-catenin in restricted brain cell types and its potential connection to autism

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          Abstract

          Background

          Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin (αT-cat, CTNNA3) with the development of autism. Where αT-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown.

          Methods

          We used the αT-cat knockout mouse to examine the localization of αT-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss.

          Results

          We found that αT-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of αE-cat expression. Notably, αT-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While αT-cat was not detected in neurons of the cerebral cortex, it was abundantly detected within neuronal structures of the molecular layer of the cerebellum. Although αT-cat loss led to no overt differences in cerebral or cerebellar structure, RNA-sequencing analysis from wild type versus knockout cerebella identified a number of disease-relevant signaling pathways associated with αT-cat loss, such as GABA-A receptor activation.

          Conclusions

          These findings raise the possibility that the genetic associations between αT-cat and autism may be due to ependymal and cerebellar defects, and highlight the potential importance of a seemingly redundant adherens junction component to a neurological disorder.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40303-016-0017-9) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          Common genetic variants on 5p14.1 associate with autism spectrum disorders.

          Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
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            ShortRead: a bioconductor package for input, quality assessment and exploration of high-throughput sequence data

            Summary: ShortRead is a package for input, quality assessment, manipulation and output of high-throughput sequencing data. ShortRead is provided in the R and Bioconductor environments, allowing ready access to additional facilities for advanced statistical analysis, data transformation, visualization and integration with diverse genomic resources. Availability and Implementation: This package is implemented in R and available at the Bioconductor web site; the package contains a ‘vignette’ outlining typical work flows. Contact: mtmorgan@fhcrc.org
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              A GENOME-WIDE LINKAGE AND ASSOCIATION SCAN REVEALS NOVEL LOCI FOR AUTISM

              Summary Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants.
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                Author and article information

                Contributors
                (312) 503-0409 , (312) 503-0411 , sai@fsm.northwestern.edu
                d-wilcox@fsm.northwestern.edu
                Koen.Tyberghein@irc.vib-ugent.be
                pieterdb@irc.vib-ugent.be
                warren@northwestern.edu
                jolanda.vanhengel@ugent.be
                frans.vanroy@ugent.be
                (312) 503-4123 , (312) 503-0409 , (312) 503-0411 , c-gottardi@northwestern.edu
                Journal
                J Mol Psychiatry
                J Mol Psychiatry
                Journal of Molecular Psychiatry
                BioMed Central (London )
                2049-9256
                21 June 2016
                21 June 2016
                2016
                : 4
                : 2
                Affiliations
                [ ]Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
                [ ]Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
                [ ]Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
                [ ]Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
                [ ]Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
                [ ]Department of Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
                [ ]The Driskill Graduate Training Program in Life Sciences, Northwestern University Feinberg School of Medicine, 240 East Huron St., McGaw Pavilion, M-323, Chicago, IL 60611 USA
                [ ]Department of Biomedical Molecular Biology, Molecular Cell Biology Unit, Ghent University, Ghent, Belgium
                [ ]Inflammation Research Center, Flanders Institute for Biotechnology (VIB), B-9052 Ghent, Belgium
                [ ]Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
                Article
                17
                10.1186/s40303-016-0017-9
                4915096
                27330745
                554a80d9-df2a-4667-8de0-30f46d06c6fe
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                : 7 April 2016
                : 8 June 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA060553
                Award ID: GM076561
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 15PRE21850010
                Award Recipient :
                Funded by: Research Foundation - Flanders (FWO) and the Belgian Science Policy
                Award ID: IAP7/07
                Award Recipient :
                Funded by: Research Foundation - Flanders (FWO) and the Belgian Science Policy
                Award ID: IAP7/07
                Award Recipient :
                Funded by: Research Foundation - Flanders (FWO) and the Belgian Science Policy
                Award ID: IAP7/07
                Award Recipient :
                Funded by: Research Foundation - Flanders (FWO) and the Belgian Science Policy
                Award ID: IAP7/07
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                alpha-t-catenin,adherens junction,autism,alzheimer’s disease,cerebellum,choroid plexus,ependyma,schizophrenia

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