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Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under beta-adrenergic stimulation
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SYSNO ASEP 0542926 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under beta-adrenergic stimulation Tvůrce(i) Synková, I. (CZ)
Bébarová, M. (CZ)
Andršová, I. (CZ)
Chmelíková, L. (CZ)
Švecová, O. (CZ)
Hošek, J. (CZ)
Pásek, Michal (UT-L) RID, ORCID
Vít, P. (CZ)
Valášková, I. (CZ)
Gaillyová, R. (CZ)
Navrátil, R. (CZ)
Novotný, T. (CZ)Celkový počet autorů 12 Číslo článku 3573 Zdroj.dok. Scientific Reports. - : Nature Publishing Group - ISSN 2045-2322
Roč. 11, č. 1 (2021)Poč.str. 14 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova long QT syndrome ; KCNQ1 ; mutation ; founder ; dominant negative ; delayed afterdepolarization Vědní obor RIV FA - Kardiovaskulární nemoci vč. kardiochirurgie Obor OECD 3.5 Other medical sciences Způsob publikování Open access Institucionální podpora UT-L - RVO:61388998 UT WOS 000626725200007 EID SCOPUS 85100735204 DOI 10.1038/s41598-021-81670-1 Anotace 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. Pracoviště Ústav termomechaniky Kontakt Marie Kajprová, kajprova@it.cas.cz, Tel.: 266 053 154 ; Jana Lahovská, jaja@it.cas.cz, Tel.: 266 053 823 Rok sběru 2022 Elektronická adresa https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878757/
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