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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388998%3A_____%2F21%3A00542926" target="_blank" >RIV/61388998:_____/21:00542926 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/65269705:_____/21:00074237 RIV/61989592:15640/21:73612553

Výsledek na webu

<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878757/" target="_blank" >https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878757/</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-021-81670-1" target="_blank" >10.1038/s41598-021-81670-1</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30500 - Other medical sciences

Projekt

<a href="/cs/project/NV16-30571A" target="_blank" >NV16-30571A: Klinický význam a elektrofyziologické zhodnocení mutace c.926C>T genu KCNQ1 (p.T309I) jako možné „founder mutation“ syndromu dlouhého intervalu QT</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

2045-2322

Svazek periodika

11

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

3573

Kód UT WoS článku

000626725200007

EID výsledku v databázi Scopus

2-s2.0-85100735204