{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:52:09Z","timestamp":1791640329503,"version":"4.3.4"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Variants of the <jats:italic>SCN1A<\/jats:italic> gene encoding the neuronal voltage-gated sodium channel Na<jats:sub>V<\/jats:sub>1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in <jats:italic>SCN1A<\/jats:italic> have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are <jats:italic>de novo<\/jats:italic>, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with <jats:italic>SCN1A<\/jats:italic> variants and epilepsy. We describe clinical and biophysical data of a familial <jats:italic>SCN1A<\/jats:italic> variant encoding the Na<jats:sub>V<\/jats:sub>1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of Na<jats:sub>V<\/jats:sub>1.1 and is a rare case of a familial <jats:italic>SCN1A<\/jats:italic> variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While <jats:italic>SCN1A<\/jats:italic>-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in <jats:italic>SCN1A<\/jats:italic> responsible for epilepsy.<\/jats:p>","DOI":"10.3389\/fphar.2021.788192","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T11:14:10Z","timestamp":1638443650000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function"],"prefix":"10.3389","volume":"12","author":[{"given":"Laura B.","family":"Jones","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin H.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Rosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxine","family":"Owers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deb K.","family":"Pal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Ruben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4201","DOI":"10.1113\/JP270139","article-title":"Differential Thermosensitivity in Mixed Syndrome Cardiac Sodium Channel Mutants","volume":"593","author":"Abdelsayed","year":"2015","journal-title":"J. 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