Silent mutation in long QT syndrome: Pathogenicity prediction by computer simulation

Abstract

s Congenital long QT syndrome (LQTS) is an inherited cardiac disorder characterized by prolongation of the QT interval on the surface electrocardiogram. Patients with LQTS are predisposed to ventricular tachyarrhythmias, torsade de pointes, leading to recurrent syncope and sudden cardiac death. The estimated frequency of this disorder is 1 in 2000. Currently, hundreds of mutations in 13 different enes have been described as causal to LQTS pathology, but utations in KCNQ1, KCNH2, and SCN5A genes comprise 0% of all the mutations. Among all the LQTS causal genes, KCNQ1 is by far the predominant mutation-harboring gene. The KCNQ1 gene encodes for the potassium-channel protein Kv7.1, which is responsible for the slow component of the delayed rectifier repolarizing current (IKs). Mutations nvolving the KCNQ1 gene result in a reduction in the epolarizing IKs current and prolongation of the QT interval. This reduction in IKs current could be mediated by one of the two mechanisms: 1) trafficking defect of the mutant protein, which could not be transported properly to the cell membrane and lacks incorporation into the tetrameric channel, and 2) mutant KCNQ1 makes a protein that is defective in channel function and exerts a dominant negative effect on the channel. It may be mentioned here that normal repoarization is accomplished by multiple different potassium hannels, which is a potential safety reserve for normal epolarization. In physiological situations, the pharmacological block or impairment of one single type of potassium channel does not always lead to QT interval prolongation, which depends on the severity of the mutant. In the presence of a mild/subclinical impairment of the repolarization process, an otherwise mild potassium-channel block, and/or accelerated heart rate, sudden adrenergic accentuation is thought to precipitate QT prolongation, resulting in torsades de pointes arrhythmia. Mutations in the transmembrane, linker, or pore-forming regions of the KCNQ1 (also KCNH2) gene are frequently