Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 51

Publication Record

Connections

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.
Roberts JD, Asaki SY, Mazzanti A, Bos JM, Tuleta I, Muir AR, Crotti L, Krahn AD, Kutyifa V, Shoemaker MB, Johnsrude CL, Aiba T, Marcondes L, Baban A, Udupa S, Dechert B, Fischbach P, Knight LM, Vittinghoff E, Kukavica D, Stallmeyer B, Giudicessi JR, Spazzolini C, Shimamoto K, Tadros R, Cadrin-Tourigny J, Duff HJ, Simpson CS, Roston TM, Wijeyeratne YD, El Hajjaji I, Yousif MD, Gula LJ, Leong-Sit P, Chavali N, Landstrom AP, Marcus GM, Dittmann S, Wilde AAM, Behr ER, Tfelt-Hansen J, Scheinman MM, Perez MV, Kaski JP, Gow RM, Drago F, Aziz PF, Abrams DJ, Gollob MH, Skinner JR, Shimizu W, Kaufman ES, Roden DM, Zareba W, Schwartz PJ, Schulze-Bahr E, Etheridge SP, Priori SG, Ackerman MJ
(2020) Circulation 141: 429-439
MeSH Terms: Adolescent, Adult, Death, Sudden, Cardiac, Electric Countershock, Electrocardiography, Female, Heart Arrest, Humans, Long QT Syndrome, Male, Middle Aged, Penetrance, Potassium Channels, Voltage-Gated, Registries
Show Abstract · Added March 24, 2020
BACKGROUND - Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare variants implicated in LQT5 was sought through an international multicenter collaboration.
METHODS - Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.
RESULTS - A total of 32 distinct rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], =0.590). The cumulative prevalence of the 32 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).
CONCLUSIONS - The present study suggests that putative/confirmed loss-of-function variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Arrhythmia genetics: Not dark and lite, but 50 shades of gray.
Roden DM, Glazer AM, Kroncke B
(2018) Heart Rhythm 15: 1231-1232
MeSH Terms: Arrhythmias, Cardiac, Humans, Long QT Syndrome, Phenotype, Potassium Channels, Voltage-Gated
Added March 26, 2019
0 Communities
3 Members
0 Resources
MeSH Terms
Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.
Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ
(2018) Circulation 137: 619-630
MeSH Terms: Action Potentials, Diagnostic Errors, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Heart Conduction System, Heart Rate, Humans, Long QT Syndrome, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Potassium Channels, Voltage-Gated, Predictive Value of Tests, Prognosis, Reproducibility of Results, Risk Assessment, Risk Factors
Show Abstract · Added March 24, 2020
The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.
© 2018 American Heart Association, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Azithromycin Causes a Novel Proarrhythmic Syndrome.
Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, Milne G, Tucker P, George AL, Campbell CM, Pickett RA, Shaffer CM, Chopra N, Yang T, Knollmann BC, Roden DM, Murray KT
(2017) Circ Arrhythm Electrophysiol 10:
MeSH Terms: Action Potentials, Animals, Anti-Bacterial Agents, Arrhythmias, Cardiac, Azithromycin, CHO Cells, Calcium Channel Blockers, Calcium Channels, L-Type, Cricetulus, Dose-Response Relationship, Drug, Electrocardiography, Ambulatory, Female, HEK293 Cells, Heart Rate, Humans, KCNQ1 Potassium Channel, Mice, Inbred C57BL, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying, Potassium Channels, Voltage-Gated, Rabbits, Sodium Channel Blockers, Telemetry, Time Factors, Transfection, Young Adult
Show Abstract · Added July 6, 2017
BACKGROUND - The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells.
METHODS AND RESULTS - In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC=110±3 μmol/L) and Na current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for I in cardiomyocytes. Mild block occurred for K currents representing I (CHO cells expressing hERG; IC=219±21 μmol/L) and I (CHO cells expressing KCNQ1+KCNE1; IC=184±12 μmol/L), whereas azithromycin suppressed L-type Ca currents (rabbit ventricular myocytes, IC=66.5±4 μmol/L) and I (HEK cells expressing Kir2.1, IC=44±3 μmol/L).
CONCLUSIONS - Chronic exposure to azithromycin increases cardiac Na current to promote intracellular Na loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.
© 2017 American Heart Association, Inc.
0 Communities
2 Members
0 Resources
28 MeSH Terms
Finding a Needle in a QT Interval Big Data Haystack: The Role for Orthogonal Datasets.
Roden DM, Mosley JD, Denny JC
(2016) J Am Coll Cardiol 68: 1765-1768
MeSH Terms: Ether-A-Go-Go Potassium Channels, Humans, Long QT Syndrome, Potassium Channels, Voltage-Gated, Torsades de Pointes
Added March 14, 2018
0 Communities
2 Members
0 Resources
5 MeSH Terms
KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting.
Wrobel E, Rothenberg I, Krisp C, Hundt F, Fraenzel B, Eckey K, Linders JT, Gallacher DJ, Towart R, Pott L, Pusch M, Yang T, Roden DM, Kurata HT, Schulze-Bahr E, Strutz-Seebohm N, Wolters D, Seebohm G
(2016) Nat Commun 7: 12795
MeSH Terms: Adamantane, Allosteric Regulation, Animals, Binding Sites, Cross-Linking Reagents, Humans, Ion Channel Gating, KCNQ1 Potassium Channel, Models, Molecular, Mutagenesis, Mutation, Oocytes, Potassium Channel Blockers, Potassium Channels, Voltage-Gated, Tandem Mass Spectrometry, Xenopus laevis
Show Abstract · Added March 24, 2020
Most small-molecule inhibitors of voltage-gated ion channels display poor subtype specificity because they bind to highly conserved residues located in the channel's central cavity. Using a combined approach of scanning mutagenesis, electrophysiology, chemical ligand modification, chemical cross-linking, MS/MS-analyses and molecular modelling, we provide evidence for the binding site for adamantane derivatives and their putative access pathway in Kv7.1/KCNE1 channels. The adamantane compounds, exemplified by JNJ303, are highly potent gating modifiers that bind to fenestrations that become available when KCNE1 accessory subunits are bound to Kv7.1 channels. This mode of regulation by auxiliary subunits may facilitate the future development of potent and highly subtype-specific Kv channel inhibitors.
0 Communities
1 Members
0 Resources
MeSH Terms
Structural basis for KCNE3 modulation of potassium recycling in epithelia.
Kroncke BM, Van Horn WD, Smith J, Kang C, Welch RC, Song Y, Nannemann DP, Taylor KC, Sisco NJ, George AL, Meiler J, Vanoye CG, Sanders CR
(2016) Sci Adv 2: e1501228
MeSH Terms: Animals, Chloride Channels, Computational Biology, Cystic Fibrosis, Electrophysiological Phenomena, Epithelial Cells, Humans, KCNQ1 Potassium Channel, Multiprotein Complexes, Potassium, Potassium Channels, Voltage-Gated, Protein Domains
Show Abstract · Added April 7, 2017
The single-span membrane protein KCNE3 modulates a variety of voltage-gated ion channels in diverse biological contexts. In epithelial cells, KCNE3 regulates the function of the KCNQ1 potassium ion (K(+)) channel to enable K(+) recycling coupled to transepithelial chloride ion (Cl(-)) secretion, a physiologically critical cellular transport process in various organs and whose malfunction causes diseases, such as cystic fibrosis (CF), cholera, and pulmonary edema. Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K(+) recycling. Central to this mechanism are direct interactions of KCNE3 residues at both ends of its transmembrane domain with residues on the intra- and extracellular ends of the KCNQ1 voltage-sensing domain S4 helix. These interactions appear to stabilize the activated "up" state configuration of S4, a prerequisite for full opening of the KCNQ1 channel gate. In addition, the integrative structural model was used to guide electrophysiological studies that illuminate the molecular basis for how estrogen exacerbates CF lung disease in female patients, a phenomenon known as the "CF gender gap."
1 Communities
5 Members
0 Resources
12 MeSH Terms
An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.
Brindley RL, Bauer MB, Blakely RD, Currie KPM
(2016) Neuropharmacology 110: 438-448
MeSH Terms: Adrenal Glands, Animals, Calcium, Calcium Channels, N-Type, Cations, Divalent, Cells, Cultured, Chromaffin Cells, Exocytosis, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Knockout, Potassium Channels, Voltage-Gated, Receptors, Serotonin, Serotonin, Serotonin Agents, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 22, 2016
Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT(-/-) mice this was reduced by ≈80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT(-/-) cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca(2+) channels, K(+) channels, or intracellular [Ca(2+)] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT(-/-) cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response.
Copyright © 2016 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Probing Structural Dynamics and Topology of the KCNE1 Membrane Protein in Lipid Bilayers via Site-Directed Spin Labeling and Electron Paramagnetic Resonance Spectroscopy.
Sahu ID, Craig AF, Dunagan MM, Troxel KR, Zhang R, Meiberg AG, Harmon CN, McCarrick RM, Kroncke BM, Sanders CR, Lorigan GA
(2015) Biochemistry 54: 6402-12
MeSH Terms: Amino Acid Sequence, Electron Spin Resonance Spectroscopy, Lipid Bilayers, Molecular Dynamics Simulation, Molecular Sequence Data, Mutagenesis, Site-Directed, Potassium Channels, Voltage-Gated, Protein Conformation
Show Abstract · Added November 21, 2018
KCNE1 is a single transmembrane protein that modulates the function of voltage-gated potassium channels, including KCNQ1. Hereditary mutations in the genes encoding either protein can result in diseases such as congenital deafness, long QT syndrome, ventricular tachyarrhythmia, syncope, and sudden cardiac death. Despite the biological significance of KCNE1, the structure and dynamic properties of its physiologically relevant native membrane-bound state are not fully understood. In this study, the structural dynamics and topology of KCNE1 in bilayered lipid vesicles was investigated using site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) spectroscopy. A 53-residue nitroxide EPR scan of the KCNE1 protein sequence including all 27 residues of the transmembrane domain (45-71) and 26 residues of the N- and C-termini of KCNE1 in lipid bilayered vesicles was analyzed in terms of nitroxide side-chain motion. Continuous wave-EPR spectral line shape analysis indicated the nitroxide spin label side-chains located in the KCNE1 TMD are less mobile when compared to the extracellular region of KCNE1. The EPR data also revealed that the C-terminus of KCNE1 is more mobile when compared to the N-terminus. EPR power saturation experiments were performed on 41 sites including 18 residues previously proposed to reside in the transmembrane domain (TMD) and 23 residues of the N- and C-termini to determine the topology of KCNE1 with respect to the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) lipid bilayers. The results indicated that the transmembrane domain is indeed buried within the membrane, spanning the width of the lipid bilayer. Power saturation data also revealed that the extracellular region of KCNE1 is solvent-exposed with some of the portions partially or weakly interacting with the membrane surface. These results are consistent with the previously published solution NMR structure of KCNE1 in micelles.
0 Communities
3 Members
0 Resources
MeSH Terms
Development of electron spin echo envelope modulation spectroscopy to probe the secondary structure of recombinant membrane proteins in a lipid bilayer.
Zhang R, Sahu ID, Gibson KR, Muhammad NB, Bali AP, Comer RG, Liu L, Craig AF, Mccarrick RM, Dabney-Smith C, Sanders CR, Lorigan GA
(2015) Protein Sci 24: 1707-13
MeSH Terms: Electron Spin Resonance Spectroscopy, Humans, Lipid Bilayers, Membrane Proteins, Models, Molecular, Potassium Channels, Voltage-Gated, Protein Structure, Secondary
Show Abstract · Added November 21, 2018
Membrane proteins conduct many important biological functions essential to the survival of organisms. However, due to their inherent hydrophobic nature, it is very difficult to obtain structural information on membrane-bound proteins using traditional biophysical techniques. We are developing a new approach to probe the secondary structure of membrane proteins using the pulsed EPR technique of Electron Spin Echo Envelope Modulation (ESEEM) Spectroscopy. This method has been successfully applied to model peptides made synthetically. However, in order for this ESEEM technique to be widely applicable to larger membrane protein systems with no size limitations, protein samples with deuterated residues need to be prepared via protein expression methods. For the first time, this study shows that the ESEEM approach can be used to probe the local secondary structure of a (2) H-labeled d8 -Val overexpressed membrane protein in a membrane mimetic environment. The membrane-bound human KCNE1 protein was used with a known solution NMR structure to demonstrate the applicability of this methodology. Three different α-helical regions of KCNE1 were probed: the extracellular domain (Val21), transmembrane domain (Val50), and cytoplasmic domain (Val95). These results indicated α-helical structures in all three segments, consistent with the micelle structure of KCNE1. Furthermore, KCNE1 was incorporated into a lipid bilayer and the secondary structure of the transmembrane domain (Val50) was shown to be α-helical in a more native-like environment. This study extends the application of this ESEEM approach to much larger membrane protein systems that are difficult to study with X-ray crystallography and/or NMR spectroscopy.
© 2015 The Protein Society.
0 Communities
1 Members
0 Resources
MeSH Terms