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

0542926 - ÚT 2022 RIV GB eng J - Článek v odborném periodiku
Synková, I. - Bébarová, M. - Andršová, I. - Chmelíková, L. - Švecová, O. - Hošek, J. - Pásek, Michal - Vít, P. - Valášková, I. - Gaillyová, R. - Navrátil, R. - Novotný, T.
Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under beta-adrenergic stimulation.
Scientific Reports. Roč. 11, č. 1 (2021), č. článku 3573. ISSN 2045-2322. E-ISSN 2045-2322
Institucionální podpora: RVO:61388998
Klíčová slova: long QT syndrome * KCNQ1 * mutation * founder * dominant negative * delayed afterdepolarization
Obor OECD: 3.5 Other medical sciences
Impakt faktor: 4.997, rok: 2021
Způsob publikování: Open access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878757/

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.
Trvalý link: http://hdl.handle.net/11104/0320267