Abstract
The variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.
Highlights
Long QT syndrome (LQTS), the most often diagnosed familial electrical disease of the heart[1], is characterised by a prolonged QTc interval and occurrence of polymorphic ventricular tachycardias of the torsades de pointes (TdP) type, degenerating into ventricular fibrillation in extreme cases
This study is a complex analysis of the c.926C > T variant (p.Thr309Ile or T309I), the first founder mutation in the KCNQ1 gene in Central Europe
All of the 4 syncopes and 2 aborted cardiac arrests (ACA) which were reported in the investigated T309I carriers appeared during physical exertion
Summary
Long QT syndrome (LQTS), the most often diagnosed familial electrical disease of the heart[1], is characterised by a prolonged QTc interval and occurrence of polymorphic ventricular tachycardias of the torsades de pointes (TdP) type, degenerating into ventricular fibrillation in extreme cases. It results in syncopes or sudden cardiac deaths. Several founder mutations in the KCNQ1 gene associated with LQTS have been reported[7,8,9,10,11,12,13,14,15,16,17,18,19]. Based on the acquired functional data, the underlying arrhythmogenic mechanism and possible alternative therapeutic way of its prevention were predicted by in silico modelling in a human ventricular cell model
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