The roles of ion channels in an inherited heart disease: molecular genetics of the long QT syndrome

Molecular genetics has revolutionized approaches to the detection management, and possible cure, of inherited diseases. The discovery of ion channel gene defects, SCN5A on chromosome 3 and HERG on chromosome 7, that underlie specific forms of the long QT syndrome (LQTS) 1-3 represents a major achievement in the understanding and potential therapeutic management of this inherited cardiac arrhythmia because specific functional changes in ion channel properties have been identified. In addition to this work, mutations have also been identified in a gene, KVLQT1, which, at the time this paper is being written, has been suggested, but not yet proven, to encode yet another potassium ion channel Still another form of the disease, LQT4 has been linked to a fourth chromosomal location (4q25-27), and the identity of this mutant gene remains unknown These important achievements in molecular biology of the disease were made possible by integration of phenotypic data collected over the years by clinicians involved in management of LQTS patients and their families with the detailed knowledge of the relationship between the molecular structure and function of voltage-gated ion channels In this paper, we will review these recent findings, relate them to the basic electrophysiological parameters that are known to control the duration of the ventricular action potential, and discuss, in particular, promising recent results that suggest that improved pharmacological management of some forms of LQTS may already be emerging from this exciting work. Other aspects of the molecular genetics of LQTS have also