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

NaV1.5 channels, encoded by SCN5A, are essential for the genesis and shaping of the cardiac action potential. Gain-of-function variants in SCN5A cause long QT syndrome (LQTS), whereas loss-of-function 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 Loss-of-function MOG1 variants (E61X and E83D) cause Brugada Syndrome, but no association with LQTS has been reported. We identified the first MOG1 variant of unknown significance (g.52C>T; p.18L>F) in a proband with LQTS. We generated AAV9-mediated cardiac-specific mouse models expressing MOG1WT and MOG1L18F and 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. The MOG1L18F proband exhibited complete AV block, prolonged QT intervals, and non-sustained ventricular tachycardia under hypokalemia. MOG1L18F mice recapitulated the patient's phenotype, with QT prolongation and increased arrhythmia inducibility, which worsened upon hypokalemia. Voltage-clamp recordings revealed a marked increase in the late sodium current (INaL) in MOG1L18F, accompanied by NaV1.8 expression enhancement in the sarcolemma. Current-clamp and optical mapping demonstrated pronounced APD prolongation at low stimulation frequencies and a steep APD restitution curve in MOG1L18F, associated with frequent early and delayed afterdepolarizations and triggered activity. Notably, the NaV1.8 inhibitor A-803467 reversed the cellular electrophysiological abnormalities, shortened the QT interval, and reduced arrhythmia inducibility in MOG1L18F mice, with no effect in MOG1WT controls. 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.