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dc.contributor.authorMoreno, Cristina-
dc.contributor.authorOliveras, Anna-
dc.contributor.authorCruz, Alicia de la-
dc.contributor.authorFelipe, Antonio-
dc.contributor.authorGonzález, Teresa-
dc.contributor.authorValenzuela, Carmen-
dc.date.accessioned2015-11-06T10:14:30Z-
dc.date.available2015-11-06T10:14:30Z-
dc.date.issued2015-
dc.identifierdoi: 10.1093/cvr/cvv196-
dc.identifierissn: 0008-6363-
dc.identifiere-issn: 1755-3245-
dc.identifier.citationCardiovascular Research 107(4): 613-623 (2015)-
dc.identifier.urihttp://hdl.handle.net/10261/124599-
dc.descriptionet al.-
dc.description.abstract[Aims]: KCNQ1 and KCNE1 encode Kv7.1 and KCNE1, respectively, the pore-forming and the accessory subunits of the slow delayed rectifier potassium current, IKs. KCNQ1 mutations are associated with long and short QT syndrome. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNQ1 missense mutation, F279I, found in a 23-year-old man with a corrected QT interval (QTc) of 356 ms and a family history of sudden cardiac death. [Methods and Results]: Experiments were performed using perforated patch-clamp, western blot, co-immunoprecipitation, biotinylation, and immunocytochemistry techniques in HEK293, COS7 cells and in cardiomyocytes transfected with WT Kv7.1/KCNE1 or F279I Kv7.1/KCNE1 channels. In the absence of KCNE1, F279I Kv7.1 current exhibited a lesser degree of inactivation than WT Kv7.1. Also, functional analysis of F279I Kv7.1 in the presence of KCNE1 revealed a negative shift in the activation curve and an acceleration of the activation kinetics leading to a gain of function in IKs. The co-assembly between F279I Kv7.1 channels and KCNE1 was markedly decreased compared with WT Kv7.1 channels, as revealed by co-immunoprecipitation and Föster Resonance Energy Transfer experiments. All these effects contribute to the increase of IKs when channels incorporate F279I Kv7.1 subunits, as shown by a computer model simulation of these data that predicts a shortening of the action potential (AP) consistent with the patient phenotype. [Conclusion]: The F279I mutation induces a gain of function of IKs due to an impaired gating modulation of Kv7.1 induced by KCNE1, leading to a shortening of the cardiac AP.-
dc.description.sponsorshipThis work was supported by the Ministerio de Economía y Competitividad (MINECO), Spain (SAF2010-14916, SAF2013-45800-R, and FIS-RIC RD12/0042/0019 to C.V. and T.G.; BFU2014-54928-R and CSD2008-00005 to A.F.; and FIS-PI11/02459 to J.R.G.). FIS Grants are funded by Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER funds. C.M. and A.O. are fellows from MINECO. T.G., N.C., and A.d.l.C. are supported by Ramón & Cajal, Juan de la Cierva, and Consejo Superior de Investigaciones Científicas contracts, respectively.-
dc.publisherOxford University Press-
dc.rightsclosedAccess-
dc.titleA new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome-
dc.typeartículo-
dc.identifier.doi10.1093/cvr/cvv196-
dc.date.updated2015-11-06T10:14:31Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderEuropean Commission-
dc.contributor.funderConsejo Superior de Investigaciones Científicas (España)-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003339es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
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