Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
| Authors | |
|---|---|
| Year of publication | 2021 |
| Type | Article in Periodical |
| Magazine / Source | Nature Scientific Reports |
| MU Faculty or unit | |
| Citation | |
| Web | https://www.nature.com/articles/s41598-021-81670-1.pdf |
| Doi | http://dx.doi.org/10.1038/s41598-021-81670-1 |
| Keywords | Long-QT founder variant T309I-Kv7.1; afterdepolarizations; ß-adrenergic stimulation |
| Description | 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 ß-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 ß-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 ß-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to ß-blocker therapy. |
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