{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:21:23Z","timestamp":1772137283449,"version":"3.50.1"},"reference-count":42,"publisher":"Proceedings of the National Academy of Sciences","issue":"28","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,7,15]]},"abstract":"<jats:p>\n                    Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1 encoded by\n                    <jats:italic>SCN1A<\/jats:italic>\n                    . We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0711717105","type":"journal-article","created":{"date-parts":[[2008,7,9]],"date-time":"2008-07-09T21:09:33Z","timestamp":1215637773000},"page":"9799-9804","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":97,"title":["Divergent sodium channel defects in familial hemiplegic migraine"],"prefix":"10.1073","volume":"105","author":[{"given":"Kristopher M.","family":"Kahlig","sequence":"first","affiliation":[{"name":"Departments of *Medicine and"}]},{"given":"Thomas H.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Departments of *Medicine and"}]},{"given":"Michael","family":"Pusch","sequence":"additional","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 16149 Genoa, Italy;"}]},{"given":"Tobias","family":"Freilinger","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ludwig-Maximilians-University, 80539 Munich, Germany;"}]},{"given":"Jos\u00e9 M.","family":"Pereira-Monteiro","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4099-002 Porto, Portugal;"},{"name":"Servi\u00e7o de Neurologia, Hospital Geral de Santo Ant\u00f3nio, 4099-001 Porto, Portugal; and"}]},{"given":"Michel D.","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Departments of \u2016Neurology and"}]},{"given":"Arn M. J. M.","family":"van den Maagdenberg","sequence":"additional","affiliation":[{"name":"Departments of \u2016Neurology and"},{"name":"**Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}]},{"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ludwig-Maximilians-University, 80539 Munich, Germany;"}]},{"suffix":"Jr.","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"Departments of *Medicine and"},{"name":"Pharmacology, Vanderbilt University, Nashville, TN 37240;"}]}],"member":"341","published-online":{"date-parts":[[2008,7,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)11370-8"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e3281338d1f"},{"key":"e_1_3_3_3_2","first-page":"1","article-title":"The International Classification of Headache Disorders","volume":"24","year":"2004","unstructured":", The International Classification of Headache Disorders. 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