The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel.

L ong QT syndrome (LQTS) is a prototypic arrhythmic disorder that is characterised by prolonged QT interval (or QTc) on electrocardiograms (ECGs), syncope, and sudden death from episodic ventricular tachyarrhythmias, specifically torsade de pointes. LQTS causes sudden deaths in young, otherwise healthy, individuals, and in many cases the first symptom is sudden death. Both genetic and acquired factors contribute to the pathogenesis of LQTS. Predisposing genetic mutations have been identified in six genes. These include the cardiac potassium channel genes KvLQT1 or KCNQ1 (chromosome 11p15.5, LQT1), HERG or KCNH2 (7q35–36, LQT2), KCNE1 (21q22, LQT5), 10 and KCNE2 (21q22, LQT6), the cardiac sodium channel gene SCN5A (3p21–24, LQT3), 13 and the non-ion channel ankyrin-B gene encoding a protein that links ion channels to the cytoskeleton (4q25–27, LQT4). Acquired long QT syndrome (aLQTS) is LQTS caused by factors such as bradycardia, cardiac ischaemia, metabolic abnormalities (including hypocalaemia and hypomagnesaemia), starvation (anorexia nervosa), and various medical manipulations and medications including general anaesthetics, antibiotics, antihistamines, and ironically antiarrhythmic agents. 16 Acquired LQTS is common, with a population prevalence rate of up to 8%. Because almost all cases of acquired LQTS are sporadic, genetic analysis of acquired LQTS has been lagging behind inherited LQTS. However, there has recently been increased interest in determining the genetic basis of acquired LQTS by studying genes causing inherited LQTS. We carried out a similar analysis in this study. Voltage gated sodium channels are transmembrane proteins responsible for generating cardiac action potentials, and for rapid conduction of electrical signals through cardiac tissues. The cardiac sodium channel is a large protein of 2016 amino acids encoded by the SCN5A gene. The cardiac sodium channel consists of a pore forming a-subunit composed of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6). SCN5A is central to the genesis of cardiac arrhythmias and sudden death, and its mutations cause inherited LQTS, idiopathic ventricular fibrillation and Brugada syndrome, and cardiac conduction disease. In this report, we have identified an SCN5A mutation, R1193Q (R/Q), in one of seven patients with acquired LQTS. Functional studies demonstrate that the electrophysiological severity of R/Q is nearly identical to two LQT3 mutations, N1325S (N/S) and R1644H (R/H), which cause susceptibility to inherited LQTS.