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

Biochemistry. 2012 Nov 13;51(45):9076-85. doi: 10.1021/bi3009449. Epub 2012 Nov 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Child
  • Female
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • KCNQ1 Potassium Channel / physiology*
  • Male
  • Middle Aged
  • Molecular Dynamics Simulation
  • Mutation, Missense
  • Potassium / metabolism*
  • Potassium Channels, Voltage-Gated / genetics
  • Risk
  • Romano-Ward Syndrome / genetics
  • Sequence Alignment

Substances

  • KCNE1 protein, human
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Potassium Channels, Voltage-Gated
  • Potassium