High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K+ permeation

Don E. Burgess, Daniel C. Bartos, Allison R. Reloj, Kenneth S. Campbell, Jonathan N. Johnson, David J. Tester, Michael J. Ackerman, Véronique Fressart, Isabelle Denjoy, Pascale Guicheney, Arthur J. Moss, Seiko Ohno, Minoru Horie, Brian P. Delisle

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Abstract

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1 gene, which encodes the K+ channel (Kv7.1) that underlies the slowly activating delayed rectifier K+ current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss of function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confers a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated nonfunctional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamics simulations of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K+-K+ repulsive forces required for rapid K+ permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K+ channel selectivity filter.

Original languageEnglish (US)
Pages (from-to)9076-9085
Number of pages10
JournalBiochemistry
Volume51
Issue number45
DOIs
StatePublished - Nov 13 2012

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Burgess, D. E., Bartos, D. C., Reloj, A. R., Campbell, K. S., Johnson, J. N., Tester, D. J., Ackerman, M. J., Fressart, V., Denjoy, I., Guicheney, P., Moss, A. J., Ohno, S., Horie, M., & Delisle, B. P. (2012). High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K+ permeation. Biochemistry, 51(45), 9076-9085. https://doi.org/10.1021/bi3009449