Probing mechanisms of long QT type 2-associated neuronal dysfunction using gene-edited stem cell-derived neurons

The overall objective of this proposal is to investigate cellular mechanisms by which long QT syndrome- associated KCNH2 variants disrupt neuronal function. hERG1, encoded by KCNH2, is a developmentally- regulated potassium channel that mediates cellular excitability. In the heart, loss-of-function KCNH2 variants cause the cardiac disorder long QT syndrome type 2 (LQTS2), and dramatically increase the likelihood of cardiac arrhythmia and sudden cardiac death. KCNH2 is also expressed in the human brain, but the mechanistic impact of KCNH2 variants on neuronal physiology has not been studied. Clinical data show that LQTS2 patients carrying KCNH2 variants develop epilepsy at five times the rate of any other LQTS-associated genes. Further, KCNH2 variants are enriched in cases of sudden unexplained death in epilepsy (SUDEP). How KCNH2 variants predispose LQTS patients to epilepsy and SUDEP has not been explored. There is therefore a critical unmet clinical need to define the mechanistic link between hERG1 potassium channel dysfunction and neuronal hyperexcitability. Here, we will use neurons differentiated from gene-edited and patient-derived human stem cells to determine molecular and cellular mechanisms by which LQTS2-associated KCNH2 variants alter neuronal function. This project will explore the confluence of cardiac and neuronal electrical activity and will provide the foundation for future R01 level-funding.