Detail publikace

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

SÝNKOVÁ, I. BÉBAROVÁ, M. ANDRŠOVÁ, I. CHMELÍKOVÁ, L. ŠVECOVÁ, O. HOŠEK, J. PÁSEK, M. VÍT, P. VALÁŠKOVÁ, I. GAILLYOVÁ, R. NAVRÁTIL, R. NOVOTNÝ, T.

Originální název

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

Typ

článek v časopise ve Web of Science, Jimp

Jazyk

angličtina

Originální abstrakt

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.

Klíčová slova

long QT syndrome, KCNQ1, mutation, founder, dominant negative, delayed 30 afterdepolarization

Autoři

SÝNKOVÁ, I.; BÉBAROVÁ, M.; ANDRŠOVÁ, I.; CHMELÍKOVÁ, L.; ŠVECOVÁ, O.; HOŠEK, J.; PÁSEK, M.; VÍT, P.; VALÁŠKOVÁ, I.; GAILLYOVÁ, R.; NAVRÁTIL, R.; NOVOTNÝ, T.

Vydáno

11. 2. 2021

Nakladatel

Nature

Místo

Spojené království Velké Británie a Severního Irska

ISSN

2045-2322

Periodikum

Scientific Reports

Ročník

11

Číslo

1

Stát

Spojené království Velké Británie a Severního Irska

Strany od

1

Strany do

13

Strany počet

13

URL

https://www.nature.com/articles/s41598-021-81670-1#Ack1

Plný text v Digitální knihovně

http://hdl.handle.net/11012/202247

BibTex

@article{BUT171501,
  author="Iva {Sýnková} and Markéta {Bébarová} and Irena {Andršová} and Larisa {Chmelíková} and Olga {Švecová} and Jan {Hošek} and Michal {Pásek} and Pavel {Vít} and Iveta {Valášková} and Renata {Gaillyová} and Rostislav {Navrátil} and Tomáš {Novotný}",
  title="Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation",
  journal="Scientific Reports",
  year="2021",
  volume="11",
  number="1",
  pages="1--13",
  doi="10.1038/s41598-021-81670-1",
  issn="2045-2322",
  url="https://www.nature.com/articles/s41598-021-81670-1#Ack1"
}