Recent advances in understanding the molecular mechanisms of the long QT syndrome

Competing theories to explain the congenital long QT syndrome have included an imbalance in sympathetic innervation of the heart or a defect in repolarizing ion currents. Recent studies have identified at least four chromosomal loci at which mutations cause the congenital long QT syndrome in different families. The specific genes mutated in affected individuals have been identified at two of these loci, and both encode cardiac ion channels. The affected genes are SCN5A, the cardiac sodium channel gene, and HERG, whose protein product likely underlies IKr, the rapidly activating delayed rectifier. Thus, currently available evidence indicates that the congenital long QT syndrome is a primary disease of cardiac ion channels. Abnormalities in either inward or outward currents can cause the disease. Ongoing studies are evaluating the function of the mutant ion channels and the relationship between individual mutations and the clinical manifestations of the syndrome.