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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F21%3A00120095" target="_blank" >RIV/00216224:14110/21:00120095 - isvavai.cz</a>

Alternative codes found

RIV/00216305:26220/21:PU140823

Result on the web

<a href="https://www.nature.com/articles/s41598-021-81670-1.pdf" target="_blank" >https://www.nature.com/articles/s41598-021-81670-1.pdf</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>

Result language

angličtina

Original language name

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

Original language description

The variant c.926C &gt; 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 &gt; 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 &gt; 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30101 - Human genetics

Project

<a href="/en/project/NV16-30571A" target="_blank" >NV16-30571A: Clinical significance and electrophysiological evaluation of KCNQ1 gene mutation c.926C>T (p.T309I) as a possible long QT syndrome founder mutation</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2021

Confidentiality

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

Name of the periodical

Nature Scientific Reports

ISSN

2045-2322

e-ISSN

—

Volume of the periodical

11

Issue of the periodical within the volume

1

Country of publishing house

DE - GERMANY

Number of pages

13

Pages from-to

1-13

UT code for WoS article

000626725200007

EID of the result in the Scopus database

2-s2.0-85100735204