0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Neurodevelopmental disorders (NDDs) include a broad spectrum of pathological conditions that affect >4% of children worldwide, share common features and present a variegated genetic origin. They include clinically defined diseases, such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), motor disorders such as Tics and Tourette’s syndromes, but also much more heterogeneous conditions like intellectual disability (ID) and epilepsy. Schizophrenia (SCZ) has also recently been proposed to belong to NDDs. Relatively common causes of NDDs are copy number variations (CNVs), characterised by the gain or the loss of a portion of a chromosome. In this review, we focus on deletions and duplications at the 16p11.2 chromosomal region, associated with NDDs, ID, ASD but also epilepsy and SCZ. Some of the core phenotypes presented by human carriers could be recapitulated in animal and cellular models, which also highlighted prominent neurophysiological and signalling alterations underpinning 16p11.2 CNVs-associated phenotypes. In this review, we also provide an overview of the genes within the 16p11.2 locus, including those with partially known or unknown function as well as non-coding RNAs. A particularly interesting interplay was observed between MVP and MAPK3 in modulating some of the pathological phenotypes associated with the 16p11.2 deletion. Elucidating their role in intracellular signalling and their functional links will be a key step to devise novel therapeutic strategies for 16p11.2 CNVs-related syndromes.

          Related collections

          Most cited references221

          • Record: found
          • Abstract: found
          • Article: not found

          Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

          Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Association between microdeletion and microduplication at 16p11.2 and autism.

            Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

              The Lancet, 381(9875), 1371-1379
                Bookmark

                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2246405/overviewRole: Role:
                URI : https://loop.frontiersin.org/people/2726376/overviewRole: Role:
                Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1129723/overviewRole: Role: Role: Role:
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                14 June 2024
                2024
                : 15
                : 1407865
                Affiliations
                [1] 1 Università di Pavia , Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani” , Pavia, Italy
                [2] 2 Cardiff University , School of Biosciences , Neuroscience and Mental Health Innovation Institute , Cardiff, United Kingdom
                Author notes

                Edited by: Harry Pantazopoulos, University of Mississippi Medical Center, United States

                Reviewed by: Luigi Balasco, University of Trento, Italy

                Simon Trent, Keele University, United Kingdom

                *Correspondence: Riccardo Brambilla, riccardo.brambilla@ 123456unipv.it ; Ilaria Morella, morellai@ 123456cardiff.ac.uk
                Article
                1407865
                10.3389/fphar.2024.1407865
                11211608
                874c93f7-47c6-44e8-aa70-76eeb6b17e4e
                Copyright © 2024 Leone, Zuglian, Brambilla and Morella.

                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
                : 27 March 2024
                : 16 May 2024
                Funding
                The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. IM was financially supported by the Medical Research Council Award (MR/S037667/1) of the “Therapeutic Target Validation in Mental Health” Programme (to RB). Work was supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)–A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).
                Categories
                Pharmacology
                Review
                Custom metadata
                Neuropharmacology

                Pharmacology & Pharmaceutical medicine
                16p11.2 cnv,basal ganglia,mapk3,neurodevelopmental disorders,animal models,ipsc (induced pluripotent stem cell),excitation/inhibition (e/i) imbalance,intellectual disability

                Comments

                Comment on this article