MULTIPLE MECHANISMS IN THE LONG-QT SYNDROME - CURRENT KNOWLEDGE, GAPS, AND FUTURE-DIRECTIONS

The congenital long-QT syndrome (LQTS) is char acterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachyc ardia. The manifestations of the disease vary, with a high incidence o f sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a card iac ion channel. In families linked to chromosome 3, mutations in SCN5 A, the. gene encoding the human cardiac sodium channel, cause the dise ase. Mutations in the human ether-g-go-go-related gene (HERG), which e ncodes a delayed-rectifier potassium channel, cause the disease in fam ilies linked to chromosome 7. Among affected individuals in families l inked to chromosome 11, mutations have been identified in KVLQT1, a ne wly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HER G mutations result in decreased outward potassium current. Either muta tion would decrease net outward current during repolarization and woul d thereby account for prolonged QT intervals on the surface EGG. Preli minary data suggest that the clinical presentation in LQTS may be dete rmined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represe nts a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at t he molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms o f susceptibility to arrhythmias in LQTS and other settings.