{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:12:40Z","timestamp":1785413560637,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,24]]},"group-title":"Physiology","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:00:00Z","timestamp":1748044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01NS121234"],"award-info":[{"award-number":["R01NS121234"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL155378"],"award-info":[{"award-number":["R01HL155378"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL148736"],"award-info":[{"award-number":["R01HL148736"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Loss-of-Function (LoF) mutations in the\n                  <jats:italic>SCN5A<\/jats:italic>\n                  gene, which encodes for the predominant cardiac Na\n                  <jats:sub>V<\/jats:sub>\n                  isoform, Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 result in either deficiency in the channel expression or function. Impaired Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 expression and function underlie reduced peak Na\n                  <jats:sup>+<\/jats:sup>\n                  current (I\n                  <jats:sub>Na<\/jats:sub>\n                  ) and result in ventricular conduction velocity slowing, predisposing the heart to conduction block and ventricular arrhythmias clinically associated with Brugada syndrome (BrS). Recently, a missense mutation in Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 selectivity filter (DEKA motif), K1419E (DE\n                  <jats:bold>E<\/jats:bold>\n                  A) has been identified in patients with BrS. Despite early characterization of mutations in selectivity filter of other Na\n                  <jats:sub>V<\/jats:sub>\n                  isoforms, little is known about the impact of DE\n                  <jats:bold>E<\/jats:bold>\n                  A on Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 function as well as on cardiac electrophysiology. Therefore, we generated a mouse heterozygous for Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 DE\n                  <jats:bold>E<\/jats:bold>\n                  A to characterize the mutation and investigate the outcome of this functionally deficient Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 variant on cardiac electrophysiology and arrhythmias. Heterologous expression system and isolated cardiomyocytes revealed lower current density and unchanged Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 expression in DE\n                  <jats:bold>E<\/jats:bold>\n                  A vs. wild type (DEKA). On the organ level, optical mapping revealed conduction velocity slowing in DE\n                  <jats:bold>E<\/jats:bold>\n                  A hearts, which was accentuated by flecainide resulting\n                  <jats:italic>in vivo<\/jats:italic>\n                  ventricular arrhythmias. Overall, to our knowledge, we provide the first mechanistic insight into the proarrhythmic consequences of a functionally deficient BrS mutation in Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Condensed abstract<\/jats:title>\n                  <jats:p>\n                    Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 mutations have been associated with life-threatening arrhythmias. Recently, a selectivity filter mutation (K1419E-Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5, DEKA\u2192DE\n                    <jats:bold>E<\/jats:bold>\n                    A), has been linked to Brugada Syndrome (BrS). While DEKA mutations in other Na\n                    <jats:sub>V<\/jats:sub>\n                    isoforms affected channel conductance, the impact of DE\n                    <jats:bold>E<\/jats:bold>\n                    A on Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 and arrhythmogenesis is unknown. Therefore, we generated mice heterozygous for Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5-DE\n                    <jats:bold>E<\/jats:bold>\n                    A. Cardiomyocytes isolated from DE\n                    <jats:bold>E<\/jats:bold>\n                    A hearts exhibited substantial reduction in sodium current, ventricular conduction slowing and susceptibility to ventricular arrhythmias in vivo that were unmasked by flecainide. Together, DE\n                    <jats:bold>E<\/jats:bold>\n                    A murine model is the first to recapitulate a functional deficiency in Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5, and thus offers insight into the proarrhythmic mechanism of BrS.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.19.654350","type":"posted-content","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T01:25:19Z","timestamp":1748136319000},"source":"Crossref","is-referenced-by-count":0,"title":["Selectivity filter mutation in Na\n                  <sub>V<\/sub>\n                  1.5 promotes ventricular tachycardia"],"prefix":"10.64898","author":[{"given":"Zoja","family":"Selimi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Tarasov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Dias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Moise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rengasayee","family":"Veeraraghavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemys\u0142aw B.","family":"Radwa\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025052800300460000_2025.05.19.654350v1.1","doi-asserted-by":"crossref","unstructured":"Li RA , Tomaselli GF , Marb\u00e1n E. 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