Missense Mutation in the Pore Region of
            <i>HERG</i>
            Causes Familial Long QT Syndrome

Dw, Benson; Ca, MacRae; Mr, Vesely; Ep, Walsh; Jg, Seidman; Ce, Seidman; Ca, Satler

doi:10.1161/01.cir.93.10.1791

Cited by 72 publications

(33 citation statements)

References 16 publications

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“…Naturally occurring mutations in HERG, producing nonfunctional channels and reduced current, underlie the chromosome 7-linked form of long Q-T syndrome (8)(9)(10)(11)(12). Afflicted individuals demonstrate prolonged Q-T intervals and experience sporadic arrhythmias, placing them at risk for sudden cardiac death.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes

Nuss¹,

Marbán²,

Johns³

1999

J. Clin. Invest.

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The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K + channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native I Kr . Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37°C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable repolarization.

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Section: Introductionmentioning

confidence: 99%

Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes

Nuss¹,

Marbán²,

Johns³

1999

J. Clin. Invest.

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“…Folding defects in this region will lead to channelopathies. For example, mutations in this region cause long QT syndrome and can be fatal (2,3). Folding of Kv channels, as with all proteins, begins as early as the birth of the nascent peptide attached to the ribosome and continues during its tenure in the endoplasmic reticulum (ER) (4)(5)(6)(7).…”

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confidence: 99%

Biogenesis of the pore architecture of a voltage-gated potassium channel

Gajewski

Dagcan

Roux

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The pore domain of voltage-gated potassium (Kv) channels consists of transmembrane helices S5 and S6, the turret, the pore helix, the selectivity filter, and the loop preceding S6, with a tertiary reentrant structure between S5 and S6. Using biogenic intermediates, mass tagging (pegylation), and a molecular tape measure, we explored the possibility that the first stages of pore formation occur prior to oligomerization of the transmembrane core. Pegylation of introduced cysteines shows that the pore helix, but not the turret, forms a compact secondary structure in the terminal 20 Å of the ribosomal tunnel. We assessed the tertiary fold of the pore loop in monomeric constructs by determining the relative accessibilities of select cysteines using the kinetics of pegylation. Turret residues are accessible at the extracellular surface. In contrast, pore helix residues are less accessible. All-atom molecular dynamics simulations of a single Kv monomer in a solvated lipid membrane indicate that secondary and tertiary folds are stable over 650 ns. These results are consistent with acquisition of a tertiary reentrant pore architecture at the monomer stage of Kv biogenesis and begin to define a plausible sequence of folding events in the formation of Kv channels.T he pore of a selective potassium channel has evolved to be highly selective and rapidly conducting. These permeation properties derive from the exquisitely precise architecture of the tetrameric channel protein (1). Voltage-gated potassium (Kv) channels have six transmembrane segments, S1-S6 and a cytosolic T1 tetramerization domain. The pore region is composed of S5, S6, and an intervening pore loop consisting of a turret, the pore helix, the selectivity filter, and a pre-S6 loop (Fig. 1). Reentry of the pore loop between S5 and S6 is necessary to position the selectivity filter facing both intra-and extracellular aqueous vestibules. The pore loop is structurally highly conserved among all ion channels. Folding defects in this region will lead to channelopathies. For example, mutations in this region cause long QT syndrome and can be fatal (2, 3). Folding of Kv channels, as with all proteins, begins as early as the birth of the nascent peptide attached to the ribosome and continues during its tenure in the endoplasmic reticulum (ER) (4-7). Yet, we know little regarding the sequence of events responsible for the critical folding of the pore itself, e.g., when are the secondary and tertiary folds that define the structure of the reentrant pore loop acquired?Here, we explore the possibility that pore structure forms early in biogenesis, in the monomer Kv1.3 channel protein. Fig. 1 (dashed circle) delineates the secondary and tertiary architecture probed in this study. Using a cysteine scan of the pore helix and turret region in a nascent (attached to the ribosome) Kv1.3 and a mass-tagging strategy, we demonstrate that compaction of the pore helix occurs in the distal portion of the ribosomal tunnel near the exit port. Using the kinetics of modification of cysteine...

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“…So far, nine mutations or deletions in HERG have been reported in patients with LQT2, including the recent report by Benson and colleagues Schulze-Bahr et al, 1995;Benson et al, 1996). By direct sequencing of HERG, we found a new missense mutation in one Japanese family with LQT…”

Section: Introductionmentioning

confidence: 56%

“…Physiological analysis of HERG have demonstrated that its gene encodes a-subunits that form channels responsible for Ikr, a cardiac delayed rectifier potassium current (Sanguinetti et al, 1995). Benson et al (1996) speculated that mutant HERG subunits may have a so-called dominant negative effect, or some mutations may result in failure of HERG assembly, thereby affecting potassium channel stoichiometry. In either case, conformational change in the amino acid may be critical to the function of HERG, which contributes to the pathophysiological basis for prolongation of repolarization.…”

Section: Discussionmentioning

confidence: 99%