{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:46:11Z","timestamp":1775634371438,"version":"3.50.1"},"reference-count":73,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":96,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004792","name":"Minist\u00e8re de l'Enseignement Sup\u00e9rieur et de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006703","name":"Universit\u00e9 de Bretagne Occidentale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006703","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007353","name":"Fondation J\u00e9r\u00f4me Lejeune","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007353","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Neurodevelopmental disorders (NDDs) encompass a wide range of conditions often linked to genetic causes, with mutations in the X\u2010linked\n                    <jats:italic>ARX<\/jats:italic>\n                    gene representing a recurrent contributor.\n                    <jats:italic>ARX<\/jats:italic>\n                    encodes a transcription factor critical for GABAergic neuron development and functioning, regulating the expression of key neurodevelopmental target genes. Variants in\n                    <jats:italic>ARX<\/jats:italic>\n                    result in a wide clinical spectrum, ranging from asymptomatic female carriers to severe developmental syndromes in both sexes. This study investigates the functional impact of 16\n                    <jats:italic>ARX<\/jats:italic>\n                    variants, including known pathogenic, likely pathogenic, and novel de novo variants, some associated with atypical presentations such as sudden infant death. Using transient expression in N2a neuroblastoma cells, we employed a comprehensive functional approach\u2014including luciferase reporter assays, Western blotting, immunofluorescence, and RT\u2010qPCR\u2014to assess protein expression levels, subcellular localization, their interaction with known corepressors (TLE1 and CtBP1), and their transcriptional activity on selected\n                    <jats:italic>ARX<\/jats:italic>\n                    \u2010known targets. Our results demonstrate that all tested variants disrupt normal\n                    <jats:italic>ARX<\/jats:italic>\n                    transcriptional function, with several also altering protein localization or expression. Remarkably, a subset of variants exhibited dominant\u2010negative effects, offering a compelling explanation for unexpectedly severe phenotypes in female patients, likely exacerbated by skewed X\u2010inactivation and other modifying factors. By integrating experimental data with a literature\u2010based review of published\n                    <jats:italic>ARX<\/jats:italic>\n                    variants, we provide refined genotype\u2013phenotype correlations, highlighting the importance of mutation type, positional context within key\n                    <jats:italic>ARX<\/jats:italic>\n                    functional domains, and patient sex. Altogether, this study advances our understanding of the molecular mechanisms driving\n                    <jats:italic>ARX<\/jats:italic>\n                    \u2010related NDDs, emphasizing the importance of functional testing for accurate variant interpretation and paving the way toward informed genetic counseling and potential therapeutic development.\n                  <\/jats:p>","DOI":"10.1155\/humu\/4732622","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T06:54:26Z","timestamp":1775631266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular Functional Analyses of\n                    <i>ARX<\/i>\n                    Variants Reveal New Insights Into Genotype\u2013Phenotype Correlations in Neurodevelopmental Disorders Among Male and Female Patients"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7915-6255","authenticated-orcid":false,"given":"Rasha","family":"Faraj","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4453-1618","authenticated-orcid":false,"given":"Audrey","family":"Farrugia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9765-9703","authenticated-orcid":false,"given":"Anna C. E.","family":"Hurst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-6494","authenticated-orcid":false,"given":"Pierre","family":"Conan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7898-9264","authenticated-orcid":false,"given":"Jennifer","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9924-870X","authenticated-orcid":false,"given":"Audrey","family":"Schalk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-1142","authenticated-orcid":false,"given":"Sylvia","family":"Redon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9279-0166","authenticated-orcid":false,"given":"Aline","family":"Dubos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2376-8026","authenticated-orcid":false,"given":"Mathilde","family":"Gras","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7823-290X","authenticated-orcid":false,"given":"Aurore","family":"Curie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7505-1927","authenticated-orcid":false,"given":"C\u00e9cile","family":"Voisset","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6681-7644","authenticated-orcid":false,"given":"Ga\u00eblle","family":"Friocourt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.17879\/freeneuropathology-2024-5734"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11070904"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20852-3"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21288"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201247"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1009"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng862"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2006.04.003"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.8.981"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbrainres.2003.11.021"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0206914"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.04629.x"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1067-08.2008"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2010.00004"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1177\/08830738050200042001"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.09.116"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008480-200312000-00004"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1017\/S001216220500023X"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10310"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-9-25"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2011.00028"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2018.04.001"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-005-0014-0"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2023-109203"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0915-09.2009"},{"key":"e_1_2_12_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy122"},{"key":"e_1_2_12_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2019.07.003"},{"key":"e_1_2_12_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23063084"},{"key":"e_1_2_12_29_2","doi-asserted-by":"publisher","DOI":"10.1097\/MS9.0000000000000197"},{"key":"e_1_2_12_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13258-018-0745-6"},{"key":"e_1_2_12_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr538"},{"key":"e_1_2_12_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2007.03.005"},{"key":"e_1_2_12_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8417-3-1"},{"key":"e_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