Pharmacological rescue of Omani long QT mutations using modulators of hERG: a study based on preliminary data

Long QT syndrome (LQTS) is a disease that affects the normal cardiac electrophysiology, predisposing affected individuals to abnormal heart rhythms and sudden death. Several types of LQTS have been reported, which include familial and acquired forms. Familial forms of LQTS have been reported in Omani patients, including LQTS type-1, -2 and -6 (Al Senaidi et al. 2014; Rajab et al. 2015; O?Callaghan et al. 2018). In a recent study (Al Salmani et al. 2022) we investigated the functional characteristics of a mutation in the ether-a-go-go related gene (hERG) that cause type-2 LQTS in an extended Omani family. hERG is a voltage dependent potassium channel whose function is essential for normal cardiac rhythm. We reported that this mutation causes channel dysfunction by modulating the gating characteristics of hERG. We suspect that multiple mechanisms cause hERG dysfunction in patients carrying the Omani T1019PfsX38 variant (Al Salmani et al. 2022). This proposal comes as a follow-up from this recent findings. We rely heavily on our expertise on studying hERG channel function. Our aim is to define the best pharmacological singular or combination treatments that can help Omani type-2 LQTS patients achieve sufficient K+ conductance to support normal heart rhythm. In addition, we will examine the pathological effects of certain physiological conditions on the function of the concerned hERG channel variant, including acidosis, alkalosis, hypokalemia, hyperkalemia, temperature variations and oxidative stress. The protective effects of certain experimental drugs will be tested as a following step. For this, we will employ molecular cloning, molecular biology, and electrophysiology to study the effects of available pharmacological modulators on hERG channel expression, stability and function under different conditions. The successful completion of this work would define tools to rescue or stabilize cardiac electrical currents in Omani type-2 LQTS patients under abnormal physiological conditions.