{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T17:57:21Z","timestamp":1766253441930,"version":"3.48.0"},"posted":{"date-parts":[[2025,12,18]]},"group-title":"Cardiovascular Medicine","reference-count":94,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 channels, encoded by\n                    <jats:italic>SCN5A<\/jats:italic>\n                    , are essential for the genesis and shaping of the cardiac action potential (AP).\n                    <jats:italic>Gain-of-function<\/jats:italic>\n                    (GoF) variants in\n                    <jats:italic>SCN5A<\/jats:italic>\n                    are associated with long QT syndrome (LQTS), whereas loss-of-function (LoF) mutations are linked with Brugada syndrome. MOG1 is an integral part of the Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 channelosome, increasing both current and membrane expression of Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5. Two LoF variants in MOG1 (E61X and E83D) cause Brugada Syndrome in patients, but no association with LQTS has been reported.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We identified the first variant of unknown significance (VUS) in MOG1 (g.52C&gt;T; p.18L&gt;F) in a proband with LQTS. We generated AAV9-mediated cardiac-specific mouse models expressing MOG1\n                    <jats:sup>WT<\/jats:sup>\n                    and MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    . We performed surface ECG, programmed electrical stimulation in live mice, optical mapping in intact hearts, and patch-clamping, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics and molecular biology assays in ventricular cardiomyocytes and HEK293 cells.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Clinical data from the MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    proband revealed complete AV block, prolonged QT intervals, and non-sustained ventricular tachycardia (nsVT) under hypokalemia. MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    mice recapitulated the patient\u2019s phenotype, with QT prolongation and an increased incidence of arrhythmia, which worsened upon hypokalemia. Voltage-clamp recordings revealed a marked increase in the late sodium current (\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>NaL<\/jats:sub>\n                    ) in MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    , accompanied by Na\n                    <jats:sub>V<\/jats:sub>\n                    1.8 expression enhancement in the sarcolemma. In current-clamp and optical mapping experiments, action potential duration (APD) increased dramatically at low stimulation frequencies resulting in a very steep APD restitution curve in MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    ventricular cardiomyocytes. This was associated with a high incidence of early and delayed afterdepolarizations (EADs and DADs, respectively) and triggered activity. Notably, the cellular electrophysiological effects of MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    were reversed by the Na\n                    <jats:sub>V<\/jats:sub>\n                    1.8 inhibitor A-803467, which also abridged the QT prolongation and reduced the arrhythmia inducibility in MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    mice, with no effect in MOG1\n                    <jats:sup>WT<\/jats:sup>\n                    mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    We have uncovered a new genetic basis for LQTS. Our findings demonstrate that the MOG1\n                    <jats:sup>L18F<\/jats:sup>\n                    variant impairs AV conduction, increases I\n                    <jats:sub>NaL<\/jats:sub>\n                    , opposes repolarizing currents, and prolongs both action potential duration and the QT interval, ultimately leading to ventricular arrhythmias, particularly under hypokalemic conditions. As Na\n                    <jats:sub>V<\/jats:sub>\n                    1.8 mediates the pathogenic I\n                    <jats:sub>NaL<\/jats:sub>\n                    increase and interacts with both MOG1 and Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5, it emerges as a promising therapeutic target.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.12.25340695","type":"posted-content","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T23:55:16Z","timestamp":1766102116000},"source":"Crossref","is-referenced-by-count":0,"title":["MOG1\n                  <sup>L18F<\/sup>\n                  -mediated increase in late sodium current produces Long QT Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-1708","authenticated-orcid":false,"given":"Paula G.","family":"Socu\u00e9llamos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0566-9315","authenticated-orcid":false,"given":"Juan Manuel","family":"Ruiz-Robles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco M.","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1lvaro","family":"Mac\u00edas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alba","family":"Vera-Zambrano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-2786","authenticated-orcid":false,"given":"Ana I","family":"Moreno-Manuel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Prior","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3429-0419","authenticated-orcid":false,"given":"Antonio J.","family":"Cart\u00f3n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3929-1960","authenticated-orcid":false,"given":"Carmen","family":"Valenzuela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0080-3500","authenticated-orcid":false,"given":"Jos\u00e9","family":"Jalife","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025122009550589000_2025.12.12.25340695v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2007.07.019"},{"key":"2025122009550589000_2025.12.12.25340695v1.2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0236"},{"key":"2025122009550589000_2025.12.12.25340695v1.3","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.hrthm.2021.11.026","article-title":"Mechanistic insights into the interaction of cardiac sodium channel Nav1.5 with MOG1 and a new molecular mechanism for Brugada syndrome","volume":"19","year":"2022","journal-title":"Heart Rhythm"},{"key":"2025122009550589000_2025.12.12.25340695v1.4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.003997"},{"key":"2025122009550589000_2025.12.12.25340695v1.5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.yjmcc.2025.06.005","article-title":"Molecular mechanism for the interaction of MOG1 with the intracellular loop II of cardiac sodium channel Nav1.5 and its role in arrhythmias","volume":"205","year":"2025","journal-title":"J. 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