Ion Channel Mechanisms Related to Sudden Cardiac Death in Phenotype-Negative Long-QT Syndrome Genotype–Phenotype Correlations of the KCNQ1(S349W) Mutation


  • This study was supported in part by research grants HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, MD.

  • No disclosures.

Addresses for correspondence: Ilan Goldenberg, M.D., Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642, USA. Fax: +1-585-273-5283; E-mail:

Coeli Lopes, Ph.D., Department of Medicine, Box CVRI, Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA. Fax: +1-585-276-9830; E-mail:


Phenotype-Negative LQTS.Background: Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype-negative long-QT syndrome (LQTS) are limited.

Methods and Results: We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc-matched carriers of haploinsufficient missense (n = 30) and nonsense (n = 45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild-type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc-matched haploinsufficent missense (21%, P = 0.004) and nonsense (25%, P = 0.01) mutations.

Conclusions: The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal-range QTc. (J Cardiovasc Electrophysiol, Vol. 22, pp. 193-200, February 2011)