Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation

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Publikace nespadá pod Fakultu sportovních studií, ale pod Lékařskou fakultu. Oficiální stránka publikace je na webu muni.cz.
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SYNKOVÁ Iva BÉBAROVÁ Markéta ANDRŠOVÁ Irena CHMELIKOVA Larisa ŠVECOVÁ Olga HOSEK Jan PÁSEK Michal VÍT Pavel VALÁŠKOVÁ Iveta GAILLYOVÁ Renata NAVRATIL Rostislav NOVOTNÝ Tomáš

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj Nature Scientific Reports
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.nature.com/articles/s41598-021-81670-1.pdf
Doi http://dx.doi.org/10.1038/s41598-021-81670-1
Klíčová slova Long-QT founder variant T309I-Kv7.1; afterdepolarizations; ß-adrenergic stimulation
Popis 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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