GENETICS, MOLECULAR MECHANISMS AND MANAGEMENT OF LONG QT SYNDROME

Cardiac arrhythmias cause more than 300000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that cause s sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chr omosome 11p15.5, HERG (LQT2) on chromosome 7q35-36, SCN5A (LQT3) on ch romosome 3p21-24, and MinK (LQT5) on chromosome 21q22. SCN5A encodes t he cardiac sodium channel, and LQT-causing mutations in SCN5A lead to the generation of a late phase of inactivation-resistant whole-cell in ward currents. Mexiletine, a sodium channel blocker, is effective in s hortening the QT interval corrected for heart rate (QTc) of patients w ith SCN5A mutations, HERG encodes the cardiac I-Kr potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of -function mechanism, Raising the serum potassium concentration can inc rease outward HERG potassium current and is effective in shortening th e QTc of patients with HERG mutations, KVLQT1 is a cardiac potassium c hannel protein that interacts with another small potassium channel Min K to form the cardiac I-Ks potassium channel. Like HERG mutations, mut ations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I-Ks potassium channel, Genetic te sting is now available for some patients with LQT.