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The congenital long QT syndrome is a rare disease in which inherited mutations of genes coding for ion channel subunits, or channel interacting proteins, delay repolarization of the human ventricle and predispose mutation carriers to the risk of serious or fatal arrhythmias. Though a rare disorder, the longQT syndrome has provided invaluable insight from studies that have bridged clinical and pre-clinical (basic science) medicine. In this brief review, we summarize some of the key clinical and genetic characteristics of this disease and highlight novel findings about ion channel structure, function, and the causal relationship between channel dysfunction and human disease, that have come from investigations of this disorder.

The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).

Cardiac conduction disorders are among the most common rhythm disturbances causing disability in millions of people worldwide and necessitating pacemaker implantation. Isolated cardiac conduction disease (ICCD) can affect various regions within the heart, and therefore the clinical features also vary from case to case. Typically, it is characterized by progressive alteration of cardiac conduction through the atrioventricular node, His-Purkinje system, with right or left bundle branch block and QRS widening. In some instances, the disorder may progress to complete atrioventricular block, with syncope and even death. While the role of genetic factors in conduction disease has been suggested as early as the 1970s, it was only recently that specific genetic loci have been reported.Multiple mutations in the gene encoding for the cardiac voltage-gated sodium channel , which plays a fundamental role in the initiation, propagation, and maintenance of normal cardiac rhythm, have been linked to conduction disease, allowing for genotype-phenotype correlation. The electrophysiological characterization of heterologously expressed mutant Na channels has revealed gating defects that consistently lead to a loss of channel function. However, studies have also revealed significant overlap between aberrant rhythm phenotypes, and single mutations have been identified that evoke multiple distinct rhythm disorders with common gating lesions. These new insights highlight the complexities involved in linking single mutations, ion-channel behavior, and cardiac rhythm but suggest that interplay between multiple factors could underlie the manifestation of the disease phenotype.

The encodes an ion channel subunit underlying , a potassium current required for the normal repolarization of ventricular cells in the human heart.Mutations in cause long QT syndrome (LQTS) by disrupting , increasing cardiac excitability and, in some cases, triggering catastrophic torsades de pointes arrhythmias and sudden death. More than 200 putative disease-causing mutations in have been identified in affected families to date, but the mechanisms by which these mutations cause disease are not well understood. Of the mutations studied, most disrupt protein maturation and reduce the numbers of hERG channels at the membrane. Some trafficking-defective mutants can be rescued by pharmacological agents or temperature. Here we review evidence for rescue of mutant hERG subunits expressed in heterologous systems and discuss the potential for therapeutic approaches to correcting defects associated with LQTS.