{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:24:25Z","timestamp":1787858665216,"version":"build-2784847793"},"reference-count":27,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>SOX4 is a transcription factor with pleiotropic functions required for different developmental processes, such as corticogenesis. As with all SOX proteins, it contains a conserved high mobility group (HMG) and exerts its function via interaction with other transcription factors, such as POU3F2. Recently, pathogenic SOX4 variants have been identified in several patients who had clinical features overlapping with Coffin\u2013Siris syndrome. In this study, we identified three novel variants in unrelated patients with intellectual disability, two of which were de novo (c.79G&gt;T, p.Glu27*; c.182G&gt;A p.Arg61Gln) and one inherited (c.355C&gt;T, p.His119Tyr). All three variants affected the HMG box and were suspected to influence SOX4 function. We investigated the effects of these variants on transcriptional activation by co-expressing either wildtype (wt) or mutant SOX4 with its co-activator POU3F2 and measuring their activity in reporter assays. All variants abolished SOX4 activity. While our experiments provide further support for the pathogenicity of SOX4 loss-of-function (LOF) variants as a cause of syndromic intellectual disability (ID), our results also indicate incomplete penetrance associated with one variant. These findings will improve classification of novel, putatively pathogenic SOX4 variants.<\/jats:p>","DOI":"10.3390\/ijms24043519","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T02:56:13Z","timestamp":1675997773000},"page":"3519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel Variants of SOX4 in Patients with Intellectual Disability"],"prefix":"10.3390","volume":"24","author":[{"given":"Martin","family":"Grosse","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 47057 Duisburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma","family":"Kuechler","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 47057 Duisburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabib","family":"Dabir","sequence":"additional","affiliation":[{"name":"Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Spranger","sequence":"additional","affiliation":[{"name":"Limbach Genetics, 28209 Bremen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Beck-W\u00f6dl","sequence":"additional","affiliation":[{"name":"Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-4836","authenticated-orcid":false,"given":"Tobias B.","family":"Haack","sequence":"additional","affiliation":[{"name":"Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Grasemann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Ruhr University of Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Manka","sequence":"additional","affiliation":[{"name":"Center for Rare Disease Essen (Essener Zentrum f\u00fcr Seltene Erkrankungen\u2014EZSE), Universit\u00e4tsmedizin Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7212-9554","authenticated-orcid":false,"given":"Christel","family":"Depienne","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 47057 Duisburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J.","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 47057 Duisburg, Germany"},{"name":"Center for Rare Disease Essen (Essener Zentrum f\u00fcr Seltene Erkrankungen\u2014EZSE), Universit\u00e4tsmedizin Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1006\/dbio.2000.9883","article-title":"Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators","volume":"227","author":"Bowles","year":"2000","journal-title":"Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4129","DOI":"10.1242\/dev.091793","article-title":"Sox proteins: Regulators of cell fate specification and differentiation","volume":"140","author":"Kamachi","year":"2013","journal-title":"Development"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1126\/science.1059157","article-title":"Cytokine-specific transcriptional regulation through an IL-5R\u03b1 interacting protein","volume":"293","author":"Geijsen","year":"2001","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16050","DOI":"10.1074\/jbc.273.26.16050","article-title":"Cooperative function of POU proteins and SOX proteins in glial cells","volume":"273","author":"Kuhlbrodt","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1093\/nar\/gkn162","article-title":"The three SoxC proteins\u2014Sox4, Sox11 and Sox12\u2014Exhibit overlapping expression patterns and molecular properties","volume":"36","author":"Dy","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.tig.2019.06.003","article-title":"SOXopathies: Growing family of developmental disorders due to SOX mutations","volume":"35","author":"Angelozzi","year":"2019","journal-title":"Trends Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1002\/j.1460-2075.1993.tb06063.x","article-title":"Sox-4, an Sry-like HMG box protein, is a transcriptional activator in lymphocytes","volume":"12","author":"Oosterwegel","year":"1993","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ajhg.2018.12.014","article-title":"De novo SOX4 variants cause a neurodevelopmental disease associated with mild dysmorphism","volume":"104","author":"Zawerton","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nature11094","article-title":"Cis-regulatory control of corticospinal system development and evolution","volume":"486","author":"Shim","year":"2012","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1038\/ncomms5011","article-title":"De novo SOX11 mutations cause Coffin\u2013Siris syndrome","volume":"5","author":"Tsurusaki","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Angelozzi, M., Karvande, A., Molin, A.N., Ritter, A.L., Leonard, J.M.M., Savatt, J.M., Douglass, K., Myers, S.M., Grippa, M., and Tolchin, D. (2022). Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome. J. Med. Genet.","DOI":"10.1136\/jmedgenet-2021-108375"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s41431-021-00968-w","article-title":"Biallelic in-frame deletion of SOX4 is associated with developmental delay, hypotonia and intellectual disability","volume":"30","author":"Ghaffar","year":"2022","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1042\/BJ20111768","article-title":"The crystal structure of the Sox4 HMG domain\u2013DNA complex suggests a mechanism for positional interdependence in DNA recognition","volume":"443","author":"Jauch","year":"2012","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.biocel.2009.09.020","article-title":"Shuttling of SOX proteins","volume":"42","author":"Malki","year":"2010","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12593","DOI":"10.1074\/jbc.R800076200","article-title":"Calmodulin-driven nuclear entry: Trigger for sex determination and terminal differentiation","volume":"284","author":"Hanover","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wilke, C.O. (2011). Transcriptional robustness complements nonsense-mediated decay in humans. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002296"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1101\/gad.269303","article-title":"Crystal structure of a POU\/HMG\/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers","volume":"17","author":"Lins","year":"2003","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/ni.2362","article-title":"The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-\u03b2 and suppresses TH 2 differentiation","volume":"13","author":"Kuwahara","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1128\/MCB.19.1.107","article-title":"Mechanism of regulatory target selection by the SOX high-mobility-group domain proteins as revealed by comparison of SOX1\/2\/3 and SOX9","volume":"19","author":"Kamachi","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1093\/hmg\/5.10.1625","article-title":"A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal","volume":"5","author":"Cameron","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1136\/jmedgenet-2011-100255","article-title":"Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development","volume":"48","author":"Benko","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_22","first-page":"1028","article-title":"Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal","volume":"57","author":"Kwok","year":"1995","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pillai-Kastoori, L., Wen, W., Wilson, S.G., Strachan, E., Lo-Castro, A., Fichera, M., Musumeci, S.A., Lehmann, O.J., and Morris, A.C. (2014). Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004491"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/s41436-019-0657-0","article-title":"Widening of the genetic and clinical spectrum of Lamb\u2013Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency","volume":"22","author":"Zawerton","year":"2020","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajhg.2009.03.010","article-title":"DECIPHER: Database of chromosomal imbalance and phenotype in humans using ensembl resources","volume":"84","author":"Firth","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: The universal protein knowledgebase in 2021","volume":"49","author":"UniProt","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D313","DOI":"10.1093\/nar\/gkw1132","article-title":"The SWISS-MODEL Repository-new features and functionality","volume":"45","author":"Bienert","year":"2017","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3519\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:29:12Z","timestamp":1760120952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":27,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043519"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043519","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,9]]}}}