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      Autism Spectrum Disorder Genes: Disease-Related Networks and Compensatory Strategies

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          Abstract

          The mammalian brain comprises structurally and functionally distinct regions. Each of these regions has characteristic molecular mechanisms that mediate higher-order tasks, such as memory, learning, emotion, impulse, and motor control. Many genes are involved in neuronal signaling and contribute to normal brain development. Dysfunction of essential components of neural signals leads to various types of brain disorders. Autism spectrum disorder is a neurodevelopmental disorder characterized by social deficits, communication challenges, and compulsive repetitive behaviors. Long-term genetic studies have uncovered key genes associated with autism spectrum disorder, such as SH3 and multiple ankyrin repeat domains 3, methyl-CpG binding protein 2, neurexin 1, and chromodomain helicase DNA binding protein 8. In addition, disease-associated networks have been identified using animal models, and the understanding of the impact of these genes on disease susceptibility and compensation is deepening. In this review, we examine rescue strategies using key models of autism spectrum disorder.

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          Most cited references126

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          Synaptic, transcriptional, and chromatin genes disrupted in autism

          Summary The genetic architecture of autism spectrum disorder involves the interplay of common and rare variation and their impact on hundreds of genes. Using exome sequencing, analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, and a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic, transcriptional, and chromatin remodeling pathways. These include voltage-gated ion channels regulating propagation of action potentials, pacemaking, and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodelers, prominently histone post-translational modifications involving lysine methylation/demethylation.
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            Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

            Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.
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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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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                03 June 2022
                2022
                : 15
                : 922840
                Affiliations
                [1] 1Department of Life Sciences, Yeungnam University , Gyeongsan, South Korea
                [2] 2Neurodegenerative Diseases Research Group, Korea Brain Research Institute , Daegu, South Korea
                Author notes

                Edited by: Byung Chang Suh, Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea

                Reviewed by: Tetsushi Sadakata, Gunma University, Japan; Takatoshi Iijima, Tokai University, Japan

                *Correspondence: Jong Hyuk Yoon, jhyoon@ 123456kbri.re.kr

                This article was submitted to Brain Disease Mechanisms, a section of the journal Frontiers in Molecular Neuroscience

                Article
                10.3389/fnmol.2022.922840
                9206533
                35726297
                40306cac-abb1-4e2c-8dd9-5c6640a09418
                Copyright © 2022 Lim, Yoon and Song.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 April 2022
                : 17 May 2022
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 126, Pages: 12, Words: 10536
                Funding
                Funded by: National Research Foundation of Korea, doi 10.13039/501100003725;
                Award ID: 2020R1A6A3A01100511
                Award ID: 2021R1I1A3055750
                Funded by: Yeungnam University, doi 10.13039/501100002649;
                Funded by: Ministry of Science and ICT, South Korea, doi 10.13039/501100014188;
                Categories
                Molecular Neuroscience
                Review

                Neurosciences
                autism spectrum disorder,genetic mice model,pathophysiology,pharmacological restoration,genetic restoration

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