{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:42:35Z","timestamp":1791258155428,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2011,12,9]],"date-time":"2011-12-09T00:00:00Z","timestamp":1323388800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2012,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p><jats:bold>Purpose:\u2002<\/jats:bold> Dravet syndrome (DS), a devastating epileptic encephalopathy, is mostly caused by mutations of the <jats:italic>SCN1A<\/jats:italic> gene, coding for the voltage\u2010gated Na<jats:sup>+<\/jats:sup> channel Na<jats:sub>V<\/jats:sub>1.1 \u03b1 subunit. About 50% of <jats:italic>SCN1A<\/jats:italic> DS mutations truncate Na<jats:sub>V<\/jats:sub>1.1, possibly causing complete loss of its function. However, it has not been investigated yet if Na<jats:sub>V<\/jats:sub>1.1 truncated mutants are dominant negative, if they impair expression or function of wild\u2010type channels, as it has been shown for truncated mutants of other proteins (e.g., Ca<jats:sub>V<\/jats:sub> channels). We studied the effect of two DS truncated Na<jats:sub>V<\/jats:sub>1.1 mutants, R222* and R1234*, on coexpressed wild\u2010type Na<jats:sup>+<\/jats:sup> channels.<\/jats:p><jats:p><jats:bold>Methods:\u2002<\/jats:bold> We engineered R222* or R1234* in the human cDNA of Na<jats:sub>V<\/jats:sub>1.1 (hNa<jats:sub>V<\/jats:sub>1.1) and studied their effect on coexpressed wild\u2010type hNa<jats:sub>V<\/jats:sub>1.1, hNa<jats:sub>V<\/jats:sub>1.2 or hNa<jats:sub>V<\/jats:sub>1.3 cotransfecting tsA\u2010201 cells, and on hNa<jats:sub>V<\/jats:sub>1.6 transfecting an human embryonic kidney (HEK) cell line stably expressing this channel. We also studied hippocampal neurons dissociated from Na<jats:sub>V<\/jats:sub>1.1 knockout (KO) mice, an animal model of DS expressing a truncated Na<jats:sub>V<\/jats:sub>1.1 channel.<\/jats:p><jats:p><jats:bold>Key Findings:\u2002<\/jats:bold> We found no modifications of current amplitude coexpressing the truncated mutants with hNa<jats:sub>V<\/jats:sub>1.1, hNa<jats:sub>V<\/jats:sub>1.2, or hNa<jats:sub>V<\/jats:sub>1.3, but a 30% reduction coexpressing them with hNa<jats:sub>V<\/jats:sub>1.6. However, we showed that also coexpression of functional full\u2010length hNa<jats:sub>V<\/jats:sub>1.1 caused a similar reduction. Therefore, this effect should not be involved in the pathomechanism of DS. Some gating properties of hNa<jats:sub>V<\/jats:sub>1.1, hNa<jats:sub>V<\/jats:sub>1.3, and hNa<jats:sub>V<\/jats:sub>1.6 were modified, but recordings of hippocampal neurons dissociated from Na<jats:sub>V<\/jats:sub>1.1 KO mice did not show any significant modifications of these properties. Therefore, Na<jats:sub>V<\/jats:sub>1.1 truncated mutants are not dominant negative, consistent with haploinsufficiency as the cause of DS.<\/jats:p><jats:p><jats:bold>Significance:\u2002<\/jats:bold> We have better clarified the pathomechanism of DS, pointed out an important difference between pathogenic truncated Ca<jats:sub>V<\/jats:sub>2.1 mutants and hNa<jats:sub>V<\/jats:sub>1.1 ones, and shown that hNa<jats:sub>V<\/jats:sub>1.6 expression can be reduced in physiologic conditions by coexpression of hNa<jats:sub>V<\/jats:sub>1.1. Moreover, our data may provide useful information for the development of therapeutic approaches.<\/jats:p>","DOI":"10.1111\/j.1528-1167.2011.03346.x","type":"journal-article","created":{"date-parts":[[2011,12,9]],"date-time":"2011-12-09T19:26:21Z","timestamp":1323458781000},"page":"87-100","source":"Crossref","is-referenced-by-count":69,"title":["Pure haploinsufficiency for Dravet syndrome Na<sub>V<\/sub>1.1 (<i>SCN1A<\/i>) sodium channel truncating 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