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Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations
Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggeste...
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Published in: | Human molecular genetics 2021-04, Vol.30 (6), p.430-442 |
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description | Abstract
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available. |
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Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddab050</identifier><identifier>PMID: 33607653</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Angelman Syndrome - genetics ; Angelman Syndrome - pathology ; Animals ; Cell Nucleus - metabolism ; Escherichia coli - metabolism ; HEK293 Cells ; Humans ; Mice ; Mutation, Missense ; Neurons - metabolism ; Saccharomyces cerevisiae - metabolism ; Ubiquitin-Protein Ligases - chemistry ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination</subject><ispartof>Human molecular genetics, 2021-04, Vol.30 (6), p.430-442</ispartof><rights>The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-ed70cb66fa625fa1b98993ea20a978db96c6c11dfa4c28bce9f26eb78682dad13</citedby><cites>FETCH-LOGICAL-c478t-ed70cb66fa625fa1b98993ea20a978db96c6c11dfa4c28bce9f26eb78682dad13</cites><orcidid>0000-0002-3758-1297 ; 0000-0002-5730-7666 ; 0000-0002-1294-1110 ; 0000-0002-3047-3429 ; 0000-0002-3046-205X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33607653$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bossuyt, Stijn N V</creatorcontrib><creatorcontrib>Punt, A Mattijs</creatorcontrib><creatorcontrib>de Graaf, Ilona J</creatorcontrib><creatorcontrib>van den Burg, Janny</creatorcontrib><creatorcontrib>Williams, Mark G</creatorcontrib><creatorcontrib>Heussler, Helen</creatorcontrib><creatorcontrib>Elgersma, Ype</creatorcontrib><creatorcontrib>Distel, Ben</creatorcontrib><title>Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Abstract
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.</description><subject>Angelman Syndrome - genetics</subject><subject>Angelman Syndrome - pathology</subject><subject>Animals</subject><subject>Cell Nucleus - metabolism</subject><subject>Escherichia coli - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Mutation, Missense</subject><subject>Neurons - metabolism</subject><subject>Saccharomyces cerevisiae - metabolism</subject><subject>Ubiquitin-Protein Ligases - chemistry</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Ubiquitination</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><recordid>eNp9kUFrFDEYhoModq2evEtOIsjYZDKTmVyEbWlVWPBiz-Gb5JvdyEyyJpnCHvzvZtm11IsQyCHP-3xJXkLecvaJMyWudvP2yloYWMuekRVvJKtq1ovnZMWUbCqpmLwgr1L6yRiXjehekgshJOtkK1bk9yakRMNI_WImhEjvr2_FmoLJ7sHlA3WJ5h3SfUQbZufBZ2pgSXiMrP0Wpxk8TQdvY5iROl-WLUm7wJQKGePB-e1ZOruU0JfsvGTILvj0mrwYC4hvzvslub-7_XHztdp8__LtZr2pTNP1uULbMTNIOYKs2xH4oHqlBELNQHW9HZQ00nBuR2hM3Q8G1VhLHLpe9rUFy8Ul-Xzy7pdhRmvQ5wiT3kc3QzzoAE7_e-LdTm_Dg-4546Kti-DDWRDDrwVT1uUxBqcJPIYl6bpRXDVt0x1nfTyhJpavjTg-juFMHwvTpTB9LqzQ757e7JH921AB3p-AsOz_a_oD_yii0w</recordid><startdate>20210430</startdate><enddate>20210430</enddate><creator>Bossuyt, Stijn N V</creator><creator>Punt, A Mattijs</creator><creator>de Graaf, Ilona J</creator><creator>van den Burg, Janny</creator><creator>Williams, Mark G</creator><creator>Heussler, Helen</creator><creator>Elgersma, Ype</creator><creator>Distel, Ben</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3758-1297</orcidid><orcidid>https://orcid.org/0000-0002-5730-7666</orcidid><orcidid>https://orcid.org/0000-0002-1294-1110</orcidid><orcidid>https://orcid.org/0000-0002-3047-3429</orcidid><orcidid>https://orcid.org/0000-0002-3046-205X</orcidid></search><sort><creationdate>20210430</creationdate><title>Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations</title><author>Bossuyt, Stijn N V ; Punt, A Mattijs ; de Graaf, Ilona J ; van den Burg, Janny ; Williams, Mark G ; Heussler, Helen ; Elgersma, Ype ; Distel, Ben</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-ed70cb66fa625fa1b98993ea20a978db96c6c11dfa4c28bce9f26eb78682dad13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Angelman Syndrome - genetics</topic><topic>Angelman Syndrome - pathology</topic><topic>Animals</topic><topic>Cell Nucleus - metabolism</topic><topic>Escherichia coli - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Mutation, Missense</topic><topic>Neurons - metabolism</topic><topic>Saccharomyces cerevisiae - metabolism</topic><topic>Ubiquitin-Protein Ligases - chemistry</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bossuyt, Stijn N V</creatorcontrib><creatorcontrib>Punt, A Mattijs</creatorcontrib><creatorcontrib>de Graaf, Ilona J</creatorcontrib><creatorcontrib>van den Burg, Janny</creatorcontrib><creatorcontrib>Williams, Mark G</creatorcontrib><creatorcontrib>Heussler, Helen</creatorcontrib><creatorcontrib>Elgersma, Ype</creatorcontrib><creatorcontrib>Distel, Ben</creatorcontrib><collection>Oxford Academic Journals (Open Access)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bossuyt, Stijn N V</au><au>Punt, A Mattijs</au><au>de Graaf, Ilona J</au><au>van den Burg, Janny</au><au>Williams, Mark G</au><au>Heussler, Helen</au><au>Elgersma, Ype</au><au>Distel, Ben</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2021-04-30</date><risdate>2021</risdate><volume>30</volume><issue>6</issue><spage>430</spage><epage>442</epage><pages>430-442</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Abstract
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33607653</pmid><doi>10.1093/hmg/ddab050</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-3758-1297</orcidid><orcidid>https://orcid.org/0000-0002-5730-7666</orcidid><orcidid>https://orcid.org/0000-0002-1294-1110</orcidid><orcidid>https://orcid.org/0000-0002-3047-3429</orcidid><orcidid>https://orcid.org/0000-0002-3046-205X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Angelman Syndrome - genetics Angelman Syndrome - pathology Animals Cell Nucleus - metabolism Escherichia coli - metabolism HEK293 Cells Humans Mice Mutation, Missense Neurons - metabolism Saccharomyces cerevisiae - metabolism Ubiquitin-Protein Ligases - chemistry Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination |
title | Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations |
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