PubMed 23092362

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNQ1 , Kv7.1 , Slo1

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

Authors: 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

Journal, date & volume: Biochemistry, 2012 Nov 13 , 51, 9076-85

PubMed link:

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.