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

Abstract 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 mil...

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Autores principales:	Iva Synková, Markéta Bébarová, Irena Andršová, Larisa Chmelikova, Olga Švecová, Jan Hošek, Michal Pásek, Pavel Vít, Iveta Valášková, Renata Gaillyová, Rostislav Navrátil, Tomáš Novotný
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/78136d3d7b394d9da2840cbe7a5654c8
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spelling	oai:doaj.org-article:78136d3d7b394d9da2840cbe7a5654c82021-12-02T12:09:51ZLong-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation10.1038/s41598-021-81670-12045-2322https://doaj.org/article/78136d3d7b394d9da2840cbe7a5654c82021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81670-1https://doaj.org/toc/2045-2322Abstract 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.Iva SynkováMarkéta BébarováIrena AndršováLarisa ChmelikovaOlga ŠvecováJan HošekMichal PásekPavel VítIveta ValáškováRenata GaillyováRostislav NavrátilTomáš NovotnýNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Iva Synková Markéta Bébarová Irena Andršová Larisa Chmelikova Olga Švecová Jan Hošek Michal Pásek Pavel Vít Iveta Valášková Renata Gaillyová Rostislav Navrátil Tomáš Novotný Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
description	Abstract 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.
format	article
author	Iva Synková Markéta Bébarová Irena Andršová Larisa Chmelikova Olga Švecová Jan Hošek Michal Pásek Pavel Vít Iveta Valášková Renata Gaillyová Rostislav Navrátil Tomáš Novotný
author_facet	Iva Synková Markéta Bébarová Irena Andršová Larisa Chmelikova Olga Švecová Jan Hošek Michal Pásek Pavel Vít Iveta Valášková Renata Gaillyová Rostislav Navrátil Tomáš Novotný
author_sort	Iva Synková
title	Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
title_short	Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
title_full	Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
title_fullStr	Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
title_full_unstemmed	Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
title_sort	long-qt founder variant t309i-kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/78136d3d7b394d9da2840cbe7a5654c8
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Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation

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