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

J 2021

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

SYNKOVÁ, Iva, Markéta BÉBAROVÁ, Irena ANDRŠOVÁ, Larisa CHMELIKOVA, Olga ŠVECOVÁ et. al.

Základní údaje

Originální název

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

Autoři

SYNKOVÁ, Iva (203 Česká republika, domácí), Markéta BÉBAROVÁ (203 Česká republika, garant, domácí), Irena ANDRŠOVÁ (203 Česká republika, domácí), Larisa CHMELIKOVA (203 Česká republika), Olga ŠVECOVÁ (203 Česká republika, domácí), Jan HOSEK (203 Česká republika), Michal PÁSEK (203 Česká republika, domácí), Pavel VÍT (203 Česká republika, domácí), Iveta VALÁŠKOVÁ (203 Česká republika, domácí), Renata GAILLYOVÁ (203 Česká republika, domácí), Rostislav NAVRATIL (203 Česká republika) a Tomáš NOVOTNÝ (203 Česká republika, domácí)

Vydání

Nature Scientific Reports, London, NATURE RESEARCH, 2021, 2045-2322

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30101 Human genetics

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.996

Kód RIV

RIV/00216224:14110/21:00120095

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1038/s41598-021-81670-1

UT WoS

000626725200007

Klíčová slova anglicky

Long-QT founder variant T309I-Kv7.1; afterdepolarizations; β-adrenergic stimulation

Štítky

14110211, 14110317, 14110323, 14110515, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 5. 2022 08:52, Mgr. Tereza Miškechová

Anotace

V originále

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.

Návaznosti

NV16-30571A, projekt VaV

Název: Klinický význam a elektrofyziologické zhodnocení mutace c.926C>T genu KCNQ1 (p.T309I) jako možné „founder mutation“ syndromu dlouhého intervalu QT

Citovat

SYNKOVÁ, Iva, Markéta BÉBAROVÁ, Irena ANDRŠOVÁ, Larisa CHMELIKOVA, Olga ŠVECOVÁ, Jan HOSEK, Michal PÁSEK, Pavel VÍT, Iveta VALÁŠKOVÁ, Renata GAILLYOVÁ, Rostislav NAVRATIL a Tomáš NOVOTNÝ. Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation. Nature Scientific Reports. London: NATURE RESEARCH, 2021, roč. 11, č. 1, s. 1-13. ISSN 2045-2322. Dostupné z: https://dx.doi.org/10.1038/s41598-021-81670-1.

@article{1765769,
   author = {Synková, Iva and Bébarová, Markéta and Andršová, Irena and Chmelikova, Larisa and Švecová, Olga and Hosek, Jan and Pásek, Michal and Vít, Pavel and Valášková, Iveta and Gaillyová, Renata and Navratil, Rostislav and Novotný, Tomáš},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1038/s41598-021-81670-1},
   keywords = {Long-QT founder variant T309I-Kv7.1; afterdepolarizations; β-adrenergic stimulation},
   language = {eng},
   issn = {2045-2322},
   journal = {Nature Scientific Reports},
   title = {Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation},
   url = {https://www.nature.com/articles/s41598-021-81670-1.pdf},
   volume = {11},
   year = {2021}
}

TY  - JOUR
ID  - 1765769
AU  - Synková, Iva - Bébarová, Markéta - Andršová, Irena - Chmelikova, Larisa - Švecová, Olga - Hosek, Jan - Pásek, Michal - Vít, Pavel - Valášková, Iveta - Gaillyová, Renata - Navratil, Rostislav - Novotný, Tomáš
PY  - 2021
TI  - Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
JF  - Nature Scientific Reports
VL  - 11
IS  - 1
SP  - 1-13
EP  - 1-13
PB  - NATURE RESEARCH
SN  - 20452322
KW  - Long-QT founder variant T309I-Kv7.1
KW  - afterdepolarizations
KW  - β-adrenergic stimulation
UR  - https://www.nature.com/articles/s41598-021-81670-1.pdf
N2  - 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.
ER  -

SYNKOVÁ, Iva, Markéta BÉBAROVÁ, Irena ANDRŠOVÁ, Larisa CHMELIKOVA, Olga ŠVECOVÁ, Jan HOSEK, Michal PÁSEK, Pavel VÍT, Iveta VALÁŠKOVÁ, Renata GAILLYOVÁ, Rostislav NAVRATIL a Tomáš NOVOTNÝ. Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation. \textit{Nature Scientific Reports}. London: NATURE RESEARCH, 2021, roč.~11, č.~1, s.~1-13. ISSN~2045-2322. Dostupné z: https://dx.doi.org/10.1038/s41598-021-81670-1.

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