Understanding how a genetic defect causes fatal heart rhythm conditions

Elucidating the effects of a short QT syndrome “hotspot” mutation and hERG channel gating pathway modifier

Short QT syndrome (SQTS) is a life-threatening condition that causes disturbances to the normal heart rhythm (arrhythmias). It occurs because of defects in molecules called ion channels which normally ensure the heart’s electrical activity is spread through the heart in an orderly sequence. The most common mutation in SQTS affects an ion channel called hERG T618I. This genetic defect in hERG causes an abnormally high movement of potassium between heart cells, but precisely how it does this and the consequences for heart muscle cell electric activity are not completely understood. Professor Jules Hancox and team aim to understand how T618I mutation in hERG affects its function. The mutation will be genetically engineered into the hERG channel, and its effects will be studied in cells as well as computer-generated models of the hERG ion channel to understand how this specific mutation affect the structure and function of the channel. The project will also investigate whether this mutation affects the targeting of the hERG channel by common anti-arrhythmic drugs. The results will provide new insights into the role of hERG in SQTS and other types of heart rhythm conditions. It will also explain how changes to hERG affect people’s response to anti-arrhythmic drugs used in the clinic.