Informace o publikaci

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

Autoři

SYNKOVÁ Iva BÉBAROVÁ Markéta ANDRŠOVÁ Irena CHMELIKOVA Larisa ŠVECOVÁ Olga HOŠEK Jan PÁSEK Michal VÍT Pavel VALÁŠKOVÁ Iveta GAILLYOVÁ Renata NAVRÁTIL Rostislav NOVOTNÝ Tomáš

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

Lékařská fakulta

Citace
www https://www.nature.com/articles/s41598-021-81670-1
Doi http://dx.doi.org/10.1038/s41598-021-81670-1
Klíčová slova 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.

Používáte starou verzi internetového prohlížeče. Doporučujeme aktualizovat Váš prohlížeč na nejnovější verzi.

Další info