{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:35:46Z","timestamp":1786988146476,"version":"build-2736575974"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS108874"],"award-info":[{"award-number":["NS108874"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Objective<\/jats:title>\n \n Pathogenic variants in\n SCN1A<\/jats:italic>\n , which encodes the voltage\u2010gated sodium channel Na\n V<\/jats:sub>\n 1.1, are associated with multiple epilepsy syndromes exhibiting a range of clinical severity.\n SCN1A<\/jats:italic>\n variants are reported in different syndromes, including Dravet syndrome, which is associated with loss\u2010of\u2010function, whereas neonatal\/infantile\u2010onset developmental and epileptic encephalopathy (DEE) is associated with gain\u2010of\u2010function. Strategies to predict\n SCN1A<\/jats:italic>\n variant pathogenicity and dysfunction have been proposed but are limited by available training data. We investigated the functional properties of four epilepsy\u2010associated\n SCN1A<\/jats:italic>\n variants affecting the same codon and sought to correlate channel dysfunction with phenotype.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Whole\u2010cell manual patch\u2010clamp recording was performed on heterologously expressed Na\n V<\/jats:sub>\n 1.1 variants. Structural modeling of Na\n V<\/jats:sub>\n 1.1 variant proteins was conducted using AlphaFold 3.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We describe an individual with early infantile\u2010onset DEE associated with\n SCN1A<\/jats:italic>\n \u2010I1347T, and identified three additional cases from the literature or ClinVar with distinct variations of the same codon (I1347N, I1347V, I1347F). Functional studies demonstrated mixed function properties for I1347T, I1347V, and I1347F, but complete loss\u2010of\u2010function for I1347N. Structural models suggest important interactions between isoleucine\u20101347 and the sixth transmembrane helices of domains 3 and 4 that are disrupted most significantly with asparagine replacement at this position (I1347N).\n <\/jats:p>\n <\/jats:sec>\n \n Interpretation<\/jats:title>\n \n Pathogenic variants in\n SCN1A<\/jats:italic>\n involving the same codon can produce divergent functional effects. Our findings suggest that predicting specific functional effects of\n SCN1A<\/jats:italic>\n variants should not rely heavily on position in the protein.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/acn3.70344","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T14:52:14Z","timestamp":1771599134000},"page":"1628-1637","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epilepsy\u2010Associated Variants of a Single\n SCN1A<\/i>\n Codon Exhibit Divergent Functional Properties"],"prefix":"10.1002","volume":"13","author":[{"given":"Lanie N.","family":"Liebovitz","sequence":"first","affiliation":[{"name":"Department of Pharmacology Northwestern University Feinberg School of Medicine Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Northwestern University Feinberg School of Medicine Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda C.","family":"Laux","sequence":"additional","affiliation":[{"name":"Ann and Robert H Lurie Children's Hospital of Chicago Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-966X","authenticated-orcid":false,"suffix":"Jr.","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Northwestern University Feinberg School of Medicine Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14074"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17141"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00246-6"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.70057"},{"issue":"3","key":"e_1_2_12_6_1","first-page":"S17","article-title":"SCN1A\u2010Related Phenotypes: Epilepsy and Beyond","volume":"60","author":"Scheffer I. E.","year":"2019","journal-title":"Epilepsia"},{"issue":"3","key":"e_1_2_12_7_1","first-page":"S2","article-title":"Dravet Syndrome as Part of the Clinical and Genetic Spectrum of Sodium Channel Epilepsies and Encephalopathies","volume":"60","author":"Mei D.","year":"2019","journal-title":"Epilepsia"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-00418-4"},{"key":"e_1_2_12_9_1","first-page":"455","volume-title":"Swaiman's Pediatric Neurology","author":"George A. L.","year":"2025"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2017.12.007"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1173460"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac210"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17274"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay6848"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac006"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17743"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100298"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.2144\/000112243"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201912442"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP281834"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt473"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.235"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1113"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073813511300"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13461"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab321"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.156314"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202313375"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae125"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.177530"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114327"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010959"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70344","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.70344","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70344","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:05:58Z","timestamp":1786986358000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,20]]},"references-count":33,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/acn3.70344"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70344","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.10.16.682932","asserted-by":"object"}]},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,20]]},"assertion":[{"value":"2025-08-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}