{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:25:31Z","timestamp":1792005931532,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010278","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000}}],"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wiedemann-Steiner Foundation"},{"name":"Louma G. Foundation"},{"name":"Icelandic Research Fund","award":["#217988, #195835, #206806"],"award-info":[{"award-number":["#217988, #195835, #206806"]}]},{"name":"Icelandic Technology Development Fund","award":["#2010588"],"award-info":[{"award-number":["#2010588"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["#R01GM121459"],"award-info":[{"award-number":["#R01GM121459"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by\n                    <jats:italic>de novo<\/jats:italic>\n                    variants in\n                    <jats:italic>KMT2A<\/jats:italic>\n                    , which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain\u2013which mediates binding to unmethylated CpGs\u2013suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from\n                    <jats:italic>Kmt2a<\/jats:italic>\n                    -deficient mice demonstrate disrupted histone methylation (H3K4me1 and H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an\n                    <jats:italic>in silico<\/jats:italic>\n                    saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the\n                    <jats:italic>in silico<\/jats:italic>\n                    characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1010278","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T13:39:11Z","timestamp":1655818751000},"page":"e1010278","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5148-4744","authenticated-orcid":true,"given":"Tinna","family":"Reynisdottir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0629-6343","authenticated-orcid":true,"given":"Kimberley Jade","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandros","family":"Boukas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6635-6753","authenticated-orcid":true,"given":"Hans Tomas","family":"Bjornsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"issue":"2","key":"pgen.1010278.ref001","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ajhg.2012.06.008","article-title":"De Novo Mutations in MLL Cause Wiedemann-Steiner Syndrome","volume":"91","author":"Wendy D. 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Voo","year":"2000","journal-title":"Mol Cell Biol"},{"issue":"7873","key":"pgen.1010278.ref004","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J. Jumper","year":"2021","journal-title":"Nature"},{"issue":"3","key":"pgen.1010278.ref005","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.celrep.2017.06.072","article-title":"KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions","volume":"20","author":"C. Kerimoglu","year":"2017","journal-title":"Cell Reports"},{"issue":"19","key":"pgen.1010278.ref006","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.1038\/sj.emboj.7601340","article-title":"Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase","volume":"25","author":"M.D. Allen","year":"2006","journal-title":"The EMBO Journal"},{"issue":"1","key":"pgen.1010278.ref007","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nsmb.1714","article-title":"Structure of the MLL CXXC domain-DNA complex and its functional role in MLL-AF9 leukemia","volume":"17","author":"T. Cierpicki","year":"2010","journal-title":"Nature structural & molecular biology"},{"issue":"13","key":"pgen.1010278.ref008","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1242\/jcs.080523","article-title":"Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways","volume":"124","author":"A. Yokoyama","year":"2011","journal-title":"Journal of Cell Science"},{"issue":"4","key":"pgen.1010278.ref009","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.molcel.2017.04.018","article-title":"Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation","volume":"66","author":"K.M. Dorighi","year":"2017","journal-title":"Mol Cell"},{"issue":"2","key":"pgen.1010278.ref010","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s10038-018-0536-6","article-title":"A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population","volume":"64","author":"V. Faundes","year":"2019","journal-title":"Journal of Human Genetics"},{"key":"pgen.1010278.ref011","article-title":"A structural biology community assessment of AlphaFold 2 applications","author":"M. 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