A novel mutation in the KCNH2 gene associated with short QT syndrome

• Published in: Journal of molecular and cellular cardiology 2011-03, Vol.50 (3), p.433-441
• Main Authors: Sun, Yaxun, Quan, Xiao-Qing, Fromme, Samantha, Cox, Robert H, Zhang, Ping, Zhang, Li, Guo, Donglin, Guo, Jihong, Patel, Chinmay, Kowey, Peter R, Yan, Gan-Xin
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - drug therapy; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Cardiovascular; Channelopathy; Child; Electrocardiography - methods; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; Female; Genetic Testing - methods; Genetics; HEK293 Cells; HERG; Humans; IKr; Male; Middle Aged; Models, Molecular; Mutation; Pedigree; Phenotype; Quinidine - pharmacology; Sequence Analysis, DNA; Short QT syndrome; Sotalol - pharmacology; Sudden death; Tp-e/QT; Young Adult
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2010.11.017

Abstract A gain of function mutation N588K in the KCNH2 gene that encodes HERG channels has been shown to underlie the SQT1 form of short QT syndrome (SQTS). We describe a different mutation in the KCNH2 gene in a Chinese family with clinical evidence of SQTS. A Chinese family with a markedly short QT interval (QTc = 316 ± 9 ms, n = 4) and a strong family history of sudden death was investigated. Analysis of candidate genes contributing to ventricular repolarization identified a C1853T mutation in the KCNH2 gene coding for the HERG channel, resulting in an amino acid change (T618I) that was found to 100% co-segregate with the SQTS phenotype ( n = 4). Whole cell voltage clamp studies of the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady state current (146.1 ± 16.7 vs 23.8 ± 5.5 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT −78.6 ± 6.8 vs T618I −29.3 ± 1.7 mV). Kinetic analysis revealed slower inactivation rates of T618I but faster rates of recovery from inactivation. Quinidine (5 μM) and sotalol (500 μM) had similar inhibitory effects on steady currents measured at + 20 mV in WT and T618I but were less effective in inhibiting tail currents of mutant channels. The altered function of T618I-HERG channels suggests that this mutation in the KCNH2 gene is responsible for the SQTS phenotype in this family. Both quinidine and sotalol may be therapeutic options for patients with the T618I HERG mutation.