GW24-e0353 A novel mutation R397Q in KCNQ1 gene caused dilated cardiomyopathy with ventricular tachycardia and prolonged QT interval

Objectives Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death with lethal ventricular arrhythmias. So far, the genetic mutations of DCM are mainly related to the sarcomeric protein, and mutations in SCN5A which encoding μ-subunit of sodium channel also have been involved. However, KCNQ1 gene encoding in potassium channel has not been found in DCM patients. The purpose of this study was to demonstrate if DCM with ventricular tachycardia and prolonged QT interval is caused by mutation in the KCNQ1 gene. Methods Clinical features and DNA samples of DCM patients with lethal ventricular arrhythmia were collected. The candidate genes including SCN5A, KCNQ1, KCNE1 and KCNE2 were screened by the direct sequencing to look for the mutations. Whole cell patch clamp analysis of HEK293 cells expressing Wild-type and mutation KCNQ1 channel was used to investigate the channels biophysical properties. The current-voltage relationships, peak current, current density, the voltage dependence of steady-state activation and inactivation of mutated channel were investigated. Results Twelve unrelated DCM patients with lethal ventricular arrhythmia were included and clinical features were available in medical records. Three patients (25%) presented cardiac conduction system abnormality, and nine patients (75%) showed QT prolongation in ECG recordings before amiodarone therapy. A G to A missense mutation in KCNQ1 gene was identified in a 60-year-old man with concomitant DCM and incessant VT and prolonged QT interval, which is at nucleotide site 1190 that resulted in a amino-acid substitution of arginine to glutamine at amino-acid site 397 (R397Q) in the C-terminal region of KCNQ1 gene. Whole cell patch clamp analysis of HEK293 cells expressing WT and mutant KCNQ1 was used to investigate the biophysical properties of the channel. It showed that R397Q (n = 19) decreased I ks current density dramatically compared with WT (14.34 ± 1.73 vs 23.25 ± 2.31, P < 0.01). However, R397Q didn’t influence on the V0.5 and slope factor for the voltage dependence of activation comparing to WT. Meanwhile, this patient experienced recurrent VT only 20 months post radio frequency ablation (RFCA). Finally an implantable cardioverter defibrillator (ICD) was successfully implanted and he had been without complaints up to the 3 years of follow-up visit. Conclusions It was firstly reported that a loss of function in KCNQ1 gene may cause the overlapping phenotype of DCM, ventricular tachycardia and prolonged QT interval. The reduction of I ks in R397Q did not significantly change the properties of gate. It seems that RFCA is the assistant to improve the incessant ventricular arrhythmia in the patients with abnormal structure heart disease and genetic background, ICD is necessary.