title: High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation.
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.
authors.affiliation: Center for Muscle Biology, Department of Physiology, University of Kentucky, 800 Rose Street, MS508, Lexington, Kentucky 40536, United States.
authors.forename: Don E
authors.initials: DE
authors.lastname: Burgess
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bartos
authors.forename: Allison R
authors.initials: AR
authors.lastname: Reloj
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Campbell
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Johnson
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D012306:Risk; D029597:Romano-Ward Syndrome / Q000235:genetics; D016415:Sequence Alignment
chemical_list: C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium