Mechanisms of disease pathogenesis in long QT syndrome type 5

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.