Arrhythmias and sudden death remain a major public health problem. Mutations of the K+ channel HERG, the human ether-a-gogo related gene, cause the long QT syndrome (LQTS), a genetic disorder characterized by lethal ventricular arrhythmias. HERG subunits are expressed in the heart and are responsible for IKr, a K+ current important in the repolarization phase of the cardiac action potential. HERG subunits interact in-vitro with IsK (minK), a K+ channel beta-subunit that coassembles with KvLQT1 to form the cardiac current IKs. It is not known whether HERG mutations affect currents other than IKr. Patients with HERG mutations and arrhythmias can have normal QT intervals. The role of HERG in other tissues and in development is unknown. Limited access to tissue and myocytes from LQTS patients presents a major obstacle towards a full understanding of the role of HERG in the heart. We have characterized Merg1 (the mouse homolog of HERG) and engineered mice with a targeted truncation of Merg1 similar to the HERG mutations that cause LQTS. Homozygous embryos are abnormal and die between embryonic days Ell and E14. Heterozygous mice (Merg1+/-) have decreased transcript levels of Merg1; levels of minK are decreased in neonates but markedly increased in adults. Heterozygotes have prolonged QT intervals as neonates, and although the QT interval normalizes with age, the adults remain susceptible to arrhythmias when treated with the alpha1-agonist methoxamine. We will test the hypotheses that Merg1 mutations cause LQTS and arrhythmias by affecting both IKr and IKs, that the cellular mechanisms that control QT interval are in part distinct from those that lead to arrhythmias, and that Merg1 is essential for cardiovascular development. Specifically, we will 1) Correlate changes in channel expression in Merg1+/- mice of several ages to changes in cardiac K+ currents; 2) Determine whether pharmacological agents that cause arrhythmias in the mice prolong the QT interval; 3) Mate the Merg1+/-mouse to a minK-/-/lacZ mouse to identify areas of altered minK expression and the significance of the Merg1/minK interaction in-vivo; and 4) Study the effects of the loss of Merg1 on embryonic development. A better understanding of the molecular basis of cardiac electrophysiology is an essential first step towards the goal of ameliorating the diverse group of diseases known as cardiac arrhythmias. The studies proposed here will extend our knowledge of the role of the HERG gene family in normal cardiac function and help to define the mechanisms by which mutations lead to arrhythmias. Information gained from these studies may help to clarify the mechanisms of the more common arrhythmias that cause sudden death.
