{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:07:16Z","timestamp":1787731636150,"version":"build-2784847793"},"reference-count":12,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","award":["GR-2018-12366478"],"award-info":[{"award-number":["GR-2018-12366478"]}],"id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["GGP20127"],"award-info":[{"award-number":["GGP20127"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Research","award":["P20228FL2Z"],"award-info":[{"award-number":["P20228FL2Z"]}]},{"name":"Angelman Syndrome Alliance"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The human UBE3A gene encodes three isoforms of Ubiquitin E3 ligase A, which differ in their N-terminal sequence, abundance, and localization. The most abundant isoforms are the short human UBE3A isoform 1 (hUBE3A-Iso1) (80%) and the long hUBE3A-Iso3 (17%), which are highly conserved across mammals. In mouse and human neurons, UBE3A levels are most prominent in the nucleus, which is largely attributed to the abundant short hUBE3A-Iso1 which is enriched in the nucleus. In mice, the cytosolic UBE3A staining is predominantly the result of cytosolically enriched long m(ouse)UBE3A-Iso2. Despite the high sequence conservation between the long mUBE3A-Iso2 and its human ortholog hUBE3A-Iso3, we previously reported nuclear enrichment for hUBE3A-Iso3. This finding was not only surprising, but also seemed at odds with the substantial cytosolic UBE3A staining that is observed in human neurons. Here, we revisited the localization of hUBE3A-Iso3, as well as an Angelman syndrome-associated variant in the N-terminal sequence of hUBE3A-Iso3. We now conclude that hUBE3A-Iso3 isoform and its mouse ortholog mUBE3A-Iso2 show in fact a very similar mostly cytosolic localization. Our previous, erroneous, conclusions are explained by the finding that N-terminal amino acid substitutions affect the localization of these two orthologs in different ways. Specifically, amino acid substitutions at the p.Met21 position of hUBE3A-Iso3 result in a partial shift of the hUBE3A-Iso3 isoform from the cytosol to the nucleus.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf044","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T10:52:24Z","timestamp":1743245544000},"page":"1009-1016","source":"Crossref","is-referenced-by-count":2,"title":["Localization of human UBE3A isoform 3 is highly sensitive to amino acid substitutions at p.Met21 position"],"prefix":"10.1093","volume":"34","author":[{"given":"Annelot C M","family":"van Esbroeck","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC , Rotterdam, Dr. Molewaterplein 40 , 3015GD Rotterdam,","place":["The Netherlands"]},{"name":"Erasmus MC Expertise Center for Neurodevelopmental Disorders (ENCORE) , Dr. Molewaterplein 40, 3015GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob F M","family":"Verhagen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC , Rotterdam, Dr. Molewaterplein 40 , 3015GD Rotterdam,","place":["The Netherlands"]},{"name":"Erasmus MC Expertise Center for Neurodevelopmental Disorders (ENCORE) , Dr. Molewaterplein 40, 3015GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Biagioni","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano , Milan 20089 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Fossati","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano , Milan 20089 ,","place":["Italy"]},{"name":"CNR Institute of Neuroscience , section of Milan, Via Manzoni 56, Rozzano 20089 Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Distel","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC , Rotterdam, Dr. Molewaterplein 40 , 3015GD Rotterdam,","place":["The Netherlands"]},{"name":"Erasmus MC Expertise Center for Neurodevelopmental Disorders (ENCORE) , Dr. Molewaterplein 40, 3015GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ype","family":"Elgersma","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC , Rotterdam, Dr. Molewaterplein 40 , 3015GD Rotterdam,","place":["The Netherlands"]},{"name":"Erasmus MC Expertise Center for Neurodevelopmental Disorders (ENCORE) , Dr. Molewaterplein 40, 3015GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"2025060505165406000_ref1","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrneurol.2016.133","article-title":"Angelman syndrome - insights into a rare neurogenetic disorder","volume":"12","author":"Buiting","year":"2016","journal-title":"Nat Rev Neurol"},{"key":"2025060505165406000_ref2","doi-asserted-by":"crossref","first-page":"D635","DOI":"10.1093\/nar\/gkw1104","article-title":"Ensembl 2017","volume":"45","author":"Aken","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2025060505165406000_ref3","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1006\/geno.1997.4617","article-title":"The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing","volume":"41","author":"Yamamoto","year":"1997","journal-title":"Genomics"},{"key":"2025060505165406000_ref4","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1093\/hmg\/ddaa194","article-title":"Conserved UBE3A subcellular distribution between human and mice is facilitated by non-homologous isoforms","volume":"29","author":"Zampeta","year":"2020","journal-title":"Hum Mol Genet"},{"key":"2025060505165406000_ref5","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1093\/hmg\/ddaa191","article-title":"Abundance and localization of human UBE3A protein isoforms","volume":"29","author":"Sirois","year":"2020","journal-title":"Hum Mol Genet"},{"key":"2025060505165406000_ref6","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1523\/JNEUROSCI.2509-12.2013","article-title":"The Angelman syndrome protein Ube3a is required for polarized dendrite morphogenesis in pyramidal neurons","volume":"33","author":"Miao","year":"2013","journal-title":"J Neurosci"},{"key":"2025060505165406000_ref7","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/hmg\/ddm288","article-title":"The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology","volume":"17","author":"Dindot","year":"2008","journal-title":"Hum Mol Genet"},{"key":"2025060505165406000_ref8","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/cne.24063","article-title":"Subcellular organization of UBE3A in neurons","volume":"525","author":"Burette","year":"2017","journal-title":"J Comp Neurol"},{"key":"2025060505165406000_ref9","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13229-018-0238-0","article-title":"Subcellular organization of UBE3A in human cerebral cortex","volume":"9","author":"Burette","year":"2018","journal-title":"Mol Autism"},{"key":"2025060505165406000_ref10","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/s41593-019-0425-0","article-title":"Loss of nuclear UBE3A causes electrophysiological and behavioral deficits in mice and is associated with Angelman syndrome","volume":"22","author":"Avagliano Trezza","year":"2019","journal-title":"Nat Neurosci"},{"key":"2025060505165406000_ref11","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1002\/ajmg.a.38831","article-title":"Two Angelman families with unusually advanced neurodevelopment carry a start codon variant in the most highly expressed UBE3A isoform","volume":"176","author":"Sadhwani","year":"2018","journal-title":"Am J Med Genet A"},{"key":"2025060505165406000_ref12","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/0092-8674(86)90762-2","article-title":"Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes","volume":"44","author":"Kozak","year":"1986","journal-title":"Cell"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/12\/1009\/62909283\/ddaf044.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/12\/1009\/62909283\/ddaf044.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:17:00Z","timestamp":1749100620000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/34\/12\/1009\/8110871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":12,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,4,11]]},"published-print":{"date-parts":[[2025,6,4]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaf044","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.02.05.578859","asserted-by":"object"}]},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6,15]]},"published":{"date-parts":[[2025,4,11]]}}}