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Mechanisms of disease pathogenesis in long QT syndrome type 5

Harmer, SC; Wilson, AJ; Aldridge, R; Tinker, A; (2010) Mechanisms of disease pathogenesis in long QT syndrome type 5. AM J PHYSIOL-CELL PH , 298 (2) C263 - C273. 10.1152/ajpcell.00308.2009.

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Abstract

Harmer SC, Wilson AJ, Aldridge R, Tinker A. Mechanisms of disease pathogenesis in long QT syndrome type 5. Am J Physiol Cell Physiol 298: C263-C273, 2010. First published November 11, 2009; doi: 10.1152/ajpcell.00308.2009.-KCNE1 associates with the pore-forming alpha-subunit KCNQ1 to generate the slow (I-Ks) current in cardiac myocytes. Mutations in either KCNQ1 or KCNE1 can alter the biophysical properties of I-Ks and mutations in KCNE1 underlie cases of long QT syndrome type 5 (LQT5). We previously investigated a mutation in KCNE1, T58P/L59P, which causes severe attenuation of I-Ks. However, how T58P/L59P acts to disrupt I-Ks has not been determined. In this study, we investigate and compare the effects of T58P/L59P with three other LQT5 mutations (G52R, S74L, and R98W) on the biophysical properties of the current, trafficking of KCNQ1, and assembly of the I-Ks channel. G52R and T58P/L59P produce currents that lack the kinetic behavior of I-Ks. In contrast, S74L and R98W both produce I-Ks-like currents but with rightward shifted voltage dependence of activation. All of the LQT5 mutants express protein robustly, and T58P/L59P and R98W cause modest, but significant, defects in the trafficking of KCNQ1. Despite defects in trafficking, in the presence of KCNQ1, T58P/L59P and the other LQT5 mutants are present at the plasma membrane. Interestingly, in comparison to KCNE1 and the other LQT5 mutants, T58P/L59P associates only weakly with KCNQ1. In conclusion, we identify the disease mechanisms for each mutation and reveal that T58P/L59P causes disease through a novel mechanism that involves defective I-Ks complex assembly.

Type: Article
Title: Mechanisms of disease pathogenesis in long QT syndrome type 5
DOI: 10.1152/ajpcell.00308.2009
Keywords: K channel, KCNQ1, KCNE1, arrhythmia, KS POTASSIUM CHANNEL, LANGE-NIELSEN-SYNDROME, I-KS, CARDIAC-ARRHYTHMIAS, KCNQ1, MINK, MUTATIONS, SUBUNITS, TRAFFICKING, PROTEINS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Metabolism and Experi Therapeutics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute for Global Health > Infection and Population Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Health Informatics
URI: http://discovery.ucl.ac.uk/id/eprint/174237
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