A plethora of mechanisms in the HERG-related long QT syndrome. Genetics meets electrophysiology.

Abstract

See article by Nakajima et al. [15] (pages 283–293) in this issue. The ether a-go-go-related gene ( eag ) was cloned from a Drosophila mutant displaying a dance-like movement disorder on exposure to ether [1]. Homologs of eag have been cloned in mouse and rat, but not (at least yet) in human. However, a related gene, the human ether a-go-go-related gene ( HERG ) was cloned from a human hippocampal cDNA library in 1994 [2]. The function of HERG was initially obscure, but came to dramatic attention in early 1995 when Keating et al. [3] identified mutations in HERG linked to one form of the congenital long QT syndrome (LQT2), and shortly thereafter HERG was identified as the α-subunit encoding the rapid component of delayed rectifier ( I Kr) [4,5]. Thus, HERG rapidly became of interest not only to geneticists interested in LQTS, but also to cardiac physiologists and pharmacologists interested in studying I Kr and its block by drugs. Studies from multiple laboratories have now made it clear that the vast majority of drugs associated with Torsades de Pointes are also I Kr blockers [6–14]. This finding, in turn, can go a long way in explaining the similarities between the congenital and drug-induced forms of the long QT syndrome, and may have important implications for drug development. Quite independent of the long QT syndrome, the availability of a cDNA encoding the structural subunit underlying I Kr has provided a crucial reagent for biophysicists studying the normal physiology, and the pathophysiology, of the channel. Therefore, mutagenesis of HERG is proceeding along two complementary lines: directed by physiology (often targeting residues or domains known to be important in other voltage-gated channels) or by clinical genetics, as new mutations are identified and characterized in patients with LQT2. The two approaches together are developing … * Corresponding author. Division of Clinical Pharmacology, 532 Medical Research Building I, Vanderbilt University School of Medicine, 23d Ave. South at Pierce Avenue, Nashville, TN 37232-6602, USA. Tel.: +1-615-322-0067; fax: +1-615-343-4522 dan.roden{at}mcmail.vanderbilt.edu