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

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. rodenatmcmail. vanderbilt. edu