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- W2015451314 abstract "The most common type of genotype-positive Long QT syndrome (LQTS) is caused by mutations in the genes that underlie the slowly-activating delayed-rectifier K+ current in the heart (IKs). KCNQ1 and KCNE1, which encode the α- and β-subunit of IKs, respectively, are linked to autosomal dominant (Romano Ward Syndrome) and recessive (Jervell and Lange-Nielsen Syndrome or JLN) forms of LQTS. Two siblings diagnosed with JLN were found to be homozygous for the T322M-KCNQ1 missense mutation (Zhang et al., BMC Med Genet 2008). Heterologous expression of T322M-KCNQ1 with KCNE1 in HEK293 cells showed that it does not generate any current (n=6). We utilized recently published computational models of the human atrial and ventricular action potential (Abraham et al., J Mol Cell Cardiol. 2010 and Grandi, et al. J Mol Cell Cardiol. 2010) to determine the effect that T322M has on cardiac Action Potential Duration (APD) stimulated at 1 Hz. A 100% reduction of IKs resulted in a prolonged APD in the atrial simulation but not the ventricular simulation. We incorporated a beta-adrenergic stimulation component into the ventricular model and found that reducing IKs by 100% in the modified simulation increased APD. We further modified the ventricular action potential simulation to compromise ‘repolarization reserve’ by reducing the rapidly-activating delayed-rectifier K+ current or IKr component. This modification exacerbated that effect that 100% block of IKs had on ventricular APD. Based on these results we conclude that T322M prolongs the atrial APD in the absence of beta-adrenergic stimulation, and prolongs the ventricular APD in the presence of beta-adrenergic stimulation and a compromised repolarization reserve." @default.
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- W2015451314 date "2011-02-01" @default.
- W2015451314 modified "2023-09-26" @default.
- W2015451314 title "A Computational Model for the Effect that a KCNQ1 Mutation Linked to Jervell and Lange-Nielson Syndrome has on Human Cardiac Action Potential Duration" @default.
- W2015451314 doi "https://doi.org/10.1016/j.bpj.2010.12.2573" @default.
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