MOG1^L18F-mediated increase in late sodium current produces Long QT Syndrome

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Electrophysiology

Background:

• SCN5A encodes NaV1.5 channels crucial for cardiac action potential; gain-of-function variants cause LQTS, loss-of-function cause Brugada syndrome.
• MOG1 is a NaV1.5 channelosome component that enhances NaV1.5 current and membrane expression.
• While MOG1 loss-of-function variants are linked to Brugada syndrome, no association with LQTS has been reported.

Purpose of the Study:

• To investigate the role of a novel MOG1 variant (p.18L>F) identified in a patient with LQTS.
• To elucidate the functional consequences of the MOG1 L18F variant on cardiac electrophysiology and identify potential therapeutic targets.

Main Methods:

• Generated cardiac-specific mouse models using AAV9 delivery of wild-type (WT) and L18F mutant MOG1.
• Performed surface ECG, programmed electrical stimulation, optical mapping, patch-clamp electrophysiology, and molecular assays.
• Utilized a NaV1.8 inhibitor (A-803467) to assess its therapeutic potential.

Main Results:

• The MOG1 L18F proband exhibited complete AV block, QT prolongation, and ventricular tachycardia under hypokalemia.
• MOG1 L18F mice showed QT prolongation, increased arrhythmia incidence, and worsened symptoms with hypokalemia.
• MOG1 L18F caused increased late sodium current (INaL), elevated action potential duration, and triggered activity, effects reversed by NaV1.8 inhibition.

Conclusions:

• The MOG1 L18F variant represents a new genetic cause of LQTS, characterized by impaired AV conduction and increased INaL.
• This variant leads to prolonged action potential duration and QT interval, causing arrhythmias, especially under hypokalemia.
• NaV1.8 is identified as the mediator of the pathogenic INaL increase and a potential therapeutic target for this MOG1-associated LQTS.