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      Environmental Factors in Autism

      review-article
      1
      Frontiers in Psychiatry
      Frontiers Media S.A.
      zinc deficiency, immune system, cytokines, ASD, Shank3, melatonin, risk factor

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          Abstract

          Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed.

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          Most cited references112

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          De novo gene disruptions in children on the autistic spectrum.

          Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

            Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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              Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

              Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity 1,2 . We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk 3 . Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.
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                Author and article information

                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                18 January 2013
                2012
                : 3
                : 118
                Affiliations
                [1] 1WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University Ulm, Germany
                Author notes

                Edited by: Andreas Reif, University of Wuerzburg, Germany

                Reviewed by: Konrad Prasad, University of Pittsburgh School of Medicine, USA; Salvatore Carbonetto, McGill University Health Centre, Canada

                *Correspondence: Andreas M. Grabrucker, WG Molecular Analysis of Synaptopathies, Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, Ulm 89081, Germany. e-mail: andreas.grabrucker@ 123456uni-ulm.de

                This article was submitted to Frontiers in Molecular Psychiatry, a specialty of Frontiers in Psychiatry.

                Article
                10.3389/fpsyt.2012.00118
                3548163
                23346059
                8b151b36-20df-4a42-ae5f-dd4a8343871b
                Copyright © 2013 Grabrucker.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 18 September 2012
                : 28 December 2012
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 138, Pages: 13, Words: 12276
                Categories
                Psychiatry
                Review Article

                Clinical Psychology & Psychiatry
                asd,cytokines,immune system,melatonin,risk factor,shank3,zinc deficiency
                Clinical Psychology & Psychiatry
                asd, cytokines, immune system, melatonin, risk factor, shank3, zinc deficiency

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