Mechanisms of disease pathogenesis in long QT syndrome type 5.
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.
Harmer
Stephen C
SC
Department of Medicine, University College London, London, WC1E 6JJ, UK.
Wilson
Andrew J
AJ
Aldridge
Robert
R
Tinker
Andrew
A
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005838:Genotype; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008564:Membrane Potentials; D046912:Multiprotein Complexes; D009154:Mutation; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D046912:Multiprotein Complexes; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; D011188:Potassium