{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:37:15Z","timestamp":1785418635287,"version":"3.56.0"},"reference-count":24,"publisher":"Rockefeller University Press","issue":"5","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS122887"],"award-info":[{"award-number":["R01 NS122887"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lauren Arena Fund"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,7]]},"abstract":"<jats:p>Variants in KCNC1 encoding the voltage-gated potassium (K+) channel subunit KV3.1 are an emerging cause of a spectrum of neurological disease including developmental delay\/intellectual disability, ataxia, myoclonus, and epilepsy, including progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Here, we report novel biophysical properties of a recurrent de novo missense variant in KCNC1 c.1196C&amp;gt;T (p.Thr399Met) associated with epilepsy, mild developmental delay, and nonprogressive ataxia. The variant is localized to the highly conserved pore region of the channel, and voltage-clamp electrophysiological recording demonstrated a complete loss of function, as seen in more severe forms of KCNC1-related disorders. When expressed with wild-type (WT) to mimic the heterozygous state of the variant as would occur in a disease context, current density was not markedly reduced; however, resulting currents displayed a \u223c20 mV hyperpolarizing shift of the voltage dependence of activation along with slowed deactivation kinetics, consistent with gain of function. In order to better understand this \u201cdominant-positive effect\u201d exerted on the WT channel, we co-expressed the KV3.1 p.Thr399Met variant with the recurrent p.Ala421Val variant known to act via loss of function with near-complete absence of current and associated with severe KCNC1-related disease. Co-expression of the two nonfunctioning variants led to a mild rescue of K+ current compared with the KCNC1-p.Ala421Val variant alone, further supporting a dominant-positive effect. Both KCNC1-p.Thr399Met and p.Ala421Val displayed trafficking deficiency. These results suggest that inclusion of the p.Thr399Met variant in heterotetrameric KV3 channels alters the gating kinetics of WT channel subunits, and highlight the unique features of this variant. The apparent complete loss of function of the p.Thr399Met variant when expressed alone is inconsistent with the relatively mild clinical presentation of the patient, subsequently explained via the \u201cdominant-positive\u201d action when combined with WT subunits.<\/jats:p>","DOI":"10.1085\/jgp.202513962","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:20:36Z","timestamp":1780640436000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["An epilepsy-associated KV3.1 potassium channel variant acts via dominant-positive effect"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-3469","authenticated-orcid":true,"given":"Jerome","family":"Clatot","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Children\u2019s Hospital of Philadelphia 1 Division of Neurology, Department of Pediatrics, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Children\u2019s Hospital of Philadelphia 2 The Epilepsy Neurogenetics Initiative, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Center for Brain Development, Genetics, and Engineering (BRIDGE), The Children\u2019s Hospital of Philadelphia 3 , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2089-0368","authenticated-orcid":true,"given":"Hubert","family":"Monnerie","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Children\u2019s Hospital of Philadelphia 1 Division of Neurology, Department of Pediatrics, , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7734-5299","authenticated-orcid":true,"given":"Axel","family":"Panzer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03dbpxy52","id-type":"ROR","asserted-by":"publisher"}],"name":"DRK Kliniken Berlin Westend, Epilepsy Center\/Pediatric Neurology 4 , Berlin,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6127-6308","authenticated-orcid":true,"given":"Konrad","family":"Platzer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center 5 , Leipzig,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7404-735X","authenticated-orcid":true,"given":"Ethan M.","family":"Goldberg","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Children\u2019s Hospital of Philadelphia 1 Division of Neurology, Department of Pediatrics, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Children\u2019s Hospital of Philadelphia 2 The Epilepsy Neurogenetics Initiative, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"The Center for Brain Development, Genetics, and Engineering (BRIDGE), The Children\u2019s Hospital of Philadelphia 3 , Philadelphia, PA,","place":["USA"]},{"name":"The University of Pennsylvania Perelman School of Medicine 6 Department of Neurology, , Philadelphia, PA,","place":["USA"]},{"name":"The University of Pennsylvania Perelman School of Medicine 7 Department of Neuroscience, , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"2026062509364383600_bib1","doi-asserted-by":"publisher","first-page":"e148","DOI":"10.1111\/epi.17656","article-title":"A novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: \u201cPrecision medicine\u201d approach with fluoxetine","volume":"64","author":"Ambrosino","year":"2023","journal-title":"Epilepsia"},{"key":"2026062509364383600_bib2","doi-asserted-by":"publisher","first-page":"104445","DOI":"10.1016\/j.ejmg.2022.104445","article-title":"The EPIGENE network: A French initiative to harmonize and improve the nationwide diagnosis of monogenic epilepsies","volume":"65","author":"Arnaud","year":"2022","journal-title":"Eur. 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