{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:34:45Z","timestamp":1790501685907,"version":"4.1.0"},"reference-count":87,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01MH120229"],"award-info":[{"award-number":["R01MH120229"]}]},{"name":"NIH","award":["R01NS114086"],"award-info":[{"award-number":["R01NS114086"]}]},{"DOI":"10.13039\/100014370","name":"SFARI","doi-asserted-by":"crossref","award":["702556"],"award-info":[{"award-number":["702556"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH-NINDS","award":["P30 NS045892"],"award-info":[{"award-number":["P30 NS045892"]}]},{"name":"NIH-NICHD","award":["U54 HD079124"],"award-info":[{"award-number":["U54 HD079124"]}]},{"name":"NWO-ZonMw TOP","award":["91216045"],"award-info":[{"award-number":["91216045"]}]},{"name":"Dup15q Alliance","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"see below","award":["see below"],"award-info":[{"award-number":["see below"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,22]]},"abstract":"<jats:p>\n                    Chromosome 15q11.2\u2013q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the\n                    <jats:italic>UBE3A<\/jats:italic>\n                    gene is presumed to be the primary driver of Dup15q pathophysiology, given that\n                    <jats:italic>UBE3A<\/jats:italic>\n                    exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of\n                    <jats:italic>Ube3a<\/jats:italic>\n                    gene overdosage using bacterial artificial chromosome\u2013based transgenic mouse models (\n                    <jats:italic>\n                      Ube3a\n                      <jats:sup>OE<\/jats:sup>\n                    <\/jats:italic>\n                    ) that recapitulate the increases in\n                    <jats:italic>Ube3a<\/jats:italic>\n                    copy number most often observed in Dup15q. In contrast to previously published\n                    <jats:italic>Ube3a<\/jats:italic>\n                    overexpression models,\n                    <jats:italic>\n                      Ube3a\n                      <jats:sup>OE<\/jats:sup>\n                    <\/jats:italic>\n                    mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between\n                    <jats:italic>UBE3A<\/jats:italic>\n                    and other overexpressed 15q11.2\u2013q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.158953","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T14:00:48Z","timestamp":1663768848000},"source":"Crossref","is-referenced-by-count":26,"title":["Molecular and behavioral consequences of Ube3a gene overdosage in mice"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5730-7666","authenticated-orcid":true,"given":"A. Mattijs","family":"Punt","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics and Department of Neuroscience and"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Judson","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Sidorov","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-619X","authenticated-orcid":true,"given":"Brittany N.","family":"Williams","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi S.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3819-3381","authenticated-orcid":true,"given":"Sabine","family":"Belder","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Department of Neuroscience and"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dion","family":"den Hertog","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Department of Neuroscience and"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney R.","family":"Davis","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximillian S.","family":"Feygin","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick F.","family":"Lang","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrnoush Aghadavoud","family":"Jolfaei","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Department of Neuroscience and"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Curran","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-8301","authenticated-orcid":true,"given":"Wilfred F.J.","family":"van IJcken","sequence":"additional","affiliation":[{"name":"Center for Biomics, Erasmus MC, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3758-1297","authenticated-orcid":true,"given":"Ype","family":"Elgersma","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Department of Neuroscience and"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2746-9143","authenticated-orcid":true,"given":"Benjamin D.","family":"Philpot","sequence":"additional","affiliation":[{"name":"Neuroscience Center, Department of Cell Biology and Physiology, and the Carolina Institute for Developmental Disabilities and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"issue":"2","key":"B1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/BF00222722","article-title":"Deletion breakpoints associated with the Prader-Willi and Angelman syndromes (15q11-q13) are not sites of high homologous recombination","volume":"91","author":"Robinson","year":"1993","journal-title":"Hum Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.33.10.848"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980901)79:2<82::AID-AJMG2>3.0.CO;2-P"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.35.2.130"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.30.6.529"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1086\/302510"},{"issue":"3\u20134","key":"B7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1159\/000015039","article-title":"Expressed copies of the MN7 (D15F37) gene family map close to the common deletion breakpoints in the Prader-Willi\/Angelman syndromes","volume":"81","author":"Buiting","year":"1998","journal-title":"Cytogenet Cell Genet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.3.533"},{"issue":"10","key":"B9","article-title":"Erratum: Masquerading repeats: paralogous pitfalls of the human genome","volume":"8","author":"Eichler","year":"1998","journal-title":"Genome Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-6-r114"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.08.011"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.6.1025"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/gim.0b013e31822bead0"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ng0197-70"},{"issue":"4","key":"B15","first-page":"928","article-title":"Autism or atypical autism in maternally but not paternally derived proximal 15q duplication","volume":"60","author":"Cook","year":"1997","journal-title":"Am J Hum Genet"},{"issue":"4","key":"B16","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/ajmg.c.30281","article-title":"The behavioral phenotype of the idic(15) syndrome","volume":"154","author":"Battaglia","year":"2010","journal-title":"Am J Med Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1551"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-015-9134-5"},{"key":"B19"},{"issue":"103","key":"B20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scitranslmed.3002627","article-title":"Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice","volume":"3","author":"Smith","year":"2011","journal-title":"Sci Transl Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx289"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nature21678"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ng0997-75"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ng0997-12"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg106"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005993"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22800"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/373081a0"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.7.2563"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2015.00322","article-title":"From UBE3A to Angelman syndrome: a substrate perspective","volume":"9","author":"Sell","year":"2015","journal-title":"Front Neurosci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401302200"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.2.1182"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1621\/nrs.06006","article-title":"E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors","volume":"6","author":"Ramamoorthy","year":"2008","journal-title":"Nucl Recept Signal"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0110"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.132"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.024"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008054"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80596-6"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23507"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24063"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80554"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-018-0231-7"},{"key":"B43","article-title":"Enhanced transmission at the calyx of held synapse in a mouse model for Angelman syndrome","volume":"4","author":"Wang","year":"2018","journal-title":"Front Cell Neurosci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12530"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318251f537"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2016.04.001"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3758\/BF03211975"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1037\/0033-2909.112.2.218"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(84)90007-4"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2009.10.008"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ps.44.020193.002321"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.12.015"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.015"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-07-02634.2003"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2828-17.2018"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12137"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2007.00096.x"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-1848.2004.00076.x"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2004.00071.x"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2006.07.030"},{"issue":"11","key":"B61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.21769\/BioProtoc.2309","article-title":"The repeated flurothyl seizure model in mice","volume":"7","author":"Ferland","year":"2017","journal-title":"Bio-Protocol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-14-05581.1997"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3232-14.2016"},{"issue":"1","key":"B64","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1172\/JCI120816","article-title":"Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice","volume":"129","author":"Gu","year":"2019","journal-title":"J Clin Invest"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.10050"},{"issue":"2","key":"B66","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s00439-004-1127-5","article-title":"Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy","volume":"115","author":"Mann","year":"2004","journal-title":"Hum Genet"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2011.04.007"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1186\/s13039-018-0365-5"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1998.2540643.x"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M312201200"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302792110"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.517805"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddab050"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0425-0"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2509-12.2013"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.02.040"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24359-3"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.205211"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101367"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22237"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-019-0280-6"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2021.07.018"},{"issue":"2","key":"B83","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1136\/jmg.2008.061580","article-title":"Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number","volume":"46","author":"Hogart","year":"2009","journal-title":"J Med Genet"},{"issue":"1","key":"B84","doi-asserted-by":"crossref","DOI":"10.1186\/2040-2392-2-19","article-title":"Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples","volume":"12","author":"Scoles","year":"2011","journal-title":"Mol Autism"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/342281a0"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/ng0994-52"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/srep29878"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/158953\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:29:19Z","timestamp":1779146959000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/158953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,22]]},"references-count":87,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9,22]]},"published-print":{"date-parts":[[2022,9,22]]}},"alternative-id":["10.1172\/jci.insight.158953"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.158953","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,22]]},"article-number":"e158953"}}