MOG1L18F-mediated increase in late sodium current produces Long QT Syndrome.

Background: NaV1.5 channels, encoded by SCN5A, are essential for the genesis and shaping of the cardiac action potential (AP). Gain-of-function (GoF) variants in SCN5A 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 NaV1.5 channelosome, increasing both current and membrane expression of NaV1.5. Two LoF variants in MOG1 (E61X and E83D) cause Brugada Syndrome in patients, but no association with LQTS has been reported. Methods: We identified the first variant of unknown significance (VUS) in MOG1 (g.52C>T; p.18L>F) in a proband with LQTS. We generated AAV9-mediated cardiac-specific mouse models expressing MOG1WT and MOG1L18F. We performed surface ECG, programmed electrical stimulation in live mice, optical mapping in intact hearts, and patch-clamping, Ca2+ dynamics and molecular biology assays in ventricular cardiomyocytes and HEK293 cells. Results: Clinical data from the MOG1L18F proband revealed complete AV block, prolonged QT intervals, and non-sustained ventricular tachycardia (nsVT) under hypokalemia. MOG1L18F mice recapitulated the patient's 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 (I NaL) in MOG1L18F, accompanied by NaV1.8 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 MOG1L18F 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 MOG1L18F were reversed by the NaV1.8 inhibitor A-803467, which also abridged the QT prolongation and reduced the arrhythmia inducibility in MOG1L18F mice, with no effect in MOG1WT mice. Conclusion: We have uncovered a new genetic basis for LQTS. Our findings demonstrate that the MOG1L18F variant impairs AV conduction, increases INaL, opposes repolarizing currents, and prolongs both action potential duration and the QT interval, ultimately leading to ventricular arrhythmias, particularly under hypokalemic conditions. As NaV1.8 mediates the pathogenic INaL increase and interacts with both MOG1 and NaV1.5, it emerges as a promising therapeutic target.