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

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dc.contributor.authorSýnková, Ivacs
dc.contributor.authorBébarová, Markétacs
dc.contributor.authorAndršová, Irenacs
dc.contributor.authorChmelíková, Larisacs
dc.contributor.authorŠvecová, Olgacs
dc.contributor.authorHošek, Jancs
dc.contributor.authorPásek, Michalcs
dc.contributor.authorVít, Pavelcs
dc.contributor.authorValášková, Ivetacs
dc.contributor.authorGaillyová, Renatacs
dc.contributor.authorNavrátil, Rostislavcs
dc.contributor.authorNovotný, Tomášcs
dc.coverage.issue1cs
dc.coverage.volume11cs
dc.date.issued2021-02-11cs
dc.description.abstractThe 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 -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 -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 -adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to -blocker therapy.en
dc.formattextcs
dc.format.extent1-13cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationScientific Reports. 2021, vol. 11, issue 1, p. 1-13.en
dc.identifier.doi10.1038/s41598-021-81670-1cs
dc.identifier.issn2045-2322cs
dc.identifier.orcid0000-0002-3178-4202cs
dc.identifier.other171501cs
dc.identifier.researcheridD-3886-2018cs
dc.identifier.scopus57188881119cs
dc.identifier.urihttp://hdl.handle.net/11012/202247
dc.language.isoencs
dc.publisherNaturecs
dc.relation.ispartofScientific Reportscs
dc.relation.urihttps://www.nature.com/articles/s41598-021-81670-1#Ack1cs
dc.rightsCreative Commons Attribution 4.0 Internationalcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/2045-2322/cs
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/cs
dc.subjectlong QT syndromeen
dc.subjectKCNQ1en
dc.subjectmutationen
dc.subjectfounderen
dc.subjectdominant negativeen
dc.subjectdelayed 30 afterdepolarizationen
dc.titleLong-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under -adrenergic stimulationen
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-171501en
sync.item.dbtypeVAVen
sync.item.insts2025.02.03 15:39:50en
sync.item.modts2025.01.17 15:18:42en
thesis.grantorVysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií. Ústav biomedicínského inženýrstvícs
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