Pathogenesis of hERG Mutations in Human Long QT Syndrome

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 DESCRIPTION (provided by applicant): Long QT syndrome is a disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmias and sudden death. Both congenital and acquired (such as drug-induced) forms of long QT syndrome have been identified. Long QT syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene (also known as hERG1 or hERG). KCNH2 encodes the Kv11.1 K+ channel that conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. The Kv11.1 channel plays an important role in congenital and drug-induced forms of long QT syndrome. LQT2 is the second most prevalent form of congenital long QT syndrome accounting for 35 to 40% of genotyped cases of long QT syndrome. Many drugs cause drug- induced long QT syndrome by inhibition of Kv11.1 channel function. Kv11.1 channel dysfunction results in the delay in action potential repolarization, leading to QT prolongation and cardiac arrhythmias. In the previous funding period, we have identified isoform switch as a novel mechanism of Kv11.1 channel dysfunction in LQT2. We also showed that the relative expression of Kv11.1 C-terminal isoforms plays an important role in the regulation of Kv11.1 channel function, and developed an antisense approach to increase the functional Kv11.1 isoform expression. In the present application, we will study the mechanisms underling the developmental and tissue-specific regulation of Kv11.1 isoform expression and demonstrate the modulation of Kv11.1 isoform expression as a novel mechanism of drug-induced suppression of Kv11.1 channel function. In addition, we will test the antisense-induced upregulation of Kv11.1 channel function in induced pluripotent stem cell-derived cardiomyocytes and a knock-in mouse model. The specific aims of this application are: Aim 1) To study the mechanisms underlying the tissue-specific and developmental regulation of Kv11.1 isoform expression. Aim 2) To identify the modulation of the relative expression Kv11.1 isoforms as a novel mechanism of drug-induced suppression of Kv11.1 channel function. Aim 3) To study the antisense-induced upregulation of functional Kv11.1 isoform expression in LQT2 patient-specific induced pluripotent stem cell-derived cardiomyocytes that carry different KCNH2 mutations. Aim 4) To study the antisense-induced upregulation of functional Kv11.1 isoform expression in a knock-in mouse model. The knowledge gained from this study will strengthen our understanding of the molecular mechanisms of long QT syndrome and provide information directed towards the development of novel therapeutic strategies for long QT syndrome.