A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel

Dan Ye, David J. Tester, Wei Zhou, John Papagiannis, Michael John Ackerman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Cav1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC's selectivity filter. Here, we identified and characterized a pore-localizing missense variant, E1115K, that yielded a novel perturbation in the LTCC. Objective: The purpose of this study was to determine whether CACNA1C-E1115K alters the LTCC's selectivity and is the substrate for the patient's LQTS. Methods: The proband was a 14-year-old male with idiopathic QT prolongation and bradycardia. Genetic testing revealed a missense variant, CACNA1C-E1115K. The whole-cell patch clamp technique was used to measure CACNA1C-WT and -E1115K currents when heterologously expressed in TSA201 cells. Results: The CACNA1C-E1115K channel exhibited no inward calcium current. Instead, robust cardiac transient outward potassium current (Ito)-like outward currents that were blocked significantly by nifedipine were measured when 2 mM/0.1 mM extracellular/intracellular CaCl2 or 4 mM/141 mM extracellular/intracellular KCl was applied. Furthermore, when 140 mM extracellular NaCl was applied, the CACNA1C-E1115K channel revealed both robust inward persistent Na+ currents with slower inactivation and outward currents, which were also nifedipine sensitive. In contrast, CACNA1C-WT revealed only a small inward persistent Na+ current without a robust outward current. Conclusion: This CACNA1C-E1115K variant destroyed the LTCC's calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward currents and potassium-mediated outward currents. Despite the anticipated 50% reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient's LQTS and arrhythmia phenotype.

Original languageEnglish (US)
Pages (from-to)270-278
Number of pages9
JournalHeart Rhythm
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Monovalent Cations
L-Type Calcium Channels
Missense Mutation
Nifedipine
Bradycardia
Potassium
Calcium
Long QT Syndrome
Genetic Testing
Patch-Clamp Techniques
Cardiac Arrhythmias
Glutamic Acid
Sodium
Phenotype
Population
Autism Spectrum Disorder

Keywords

  • Arrhythmia
  • CACNA1C
  • Ion channel
  • L-type calcium channel
  • Long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{c303e5ff1ce8440f9ee005169583c24f,
title = "A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel",
abstract = "Background: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Cav1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC's selectivity filter. Here, we identified and characterized a pore-localizing missense variant, E1115K, that yielded a novel perturbation in the LTCC. Objective: The purpose of this study was to determine whether CACNA1C-E1115K alters the LTCC's selectivity and is the substrate for the patient's LQTS. Methods: The proband was a 14-year-old male with idiopathic QT prolongation and bradycardia. Genetic testing revealed a missense variant, CACNA1C-E1115K. The whole-cell patch clamp technique was used to measure CACNA1C-WT and -E1115K currents when heterologously expressed in TSA201 cells. Results: The CACNA1C-E1115K channel exhibited no inward calcium current. Instead, robust cardiac transient outward potassium current (Ito)-like outward currents that were blocked significantly by nifedipine were measured when 2 mM/0.1 mM extracellular/intracellular CaCl2 or 4 mM/141 mM extracellular/intracellular KCl was applied. Furthermore, when 140 mM extracellular NaCl was applied, the CACNA1C-E1115K channel revealed both robust inward persistent Na+ currents with slower inactivation and outward currents, which were also nifedipine sensitive. In contrast, CACNA1C-WT revealed only a small inward persistent Na+ current without a robust outward current. Conclusion: This CACNA1C-E1115K variant destroyed the LTCC's calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward currents and potassium-mediated outward currents. Despite the anticipated 50{\%} reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient's LQTS and arrhythmia phenotype.",
keywords = "Arrhythmia, CACNA1C, Ion channel, L-type calcium channel, Long QT syndrome",
author = "Dan Ye and Tester, {David J.} and Wei Zhou and John Papagiannis and Ackerman, {Michael John}",
year = "2019",
month = "2",
day = "1",
doi = "10.1016/j.hrthm.2018.08.030",
language = "English (US)",
volume = "16",
pages = "270--278",
journal = "Heart Rhythm",
issn = "1547-5271",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel

AU - Ye, Dan

AU - Tester, David J.

AU - Zhou, Wei

AU - Papagiannis, John

AU - Ackerman, Michael John

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Cav1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC's selectivity filter. Here, we identified and characterized a pore-localizing missense variant, E1115K, that yielded a novel perturbation in the LTCC. Objective: The purpose of this study was to determine whether CACNA1C-E1115K alters the LTCC's selectivity and is the substrate for the patient's LQTS. Methods: The proband was a 14-year-old male with idiopathic QT prolongation and bradycardia. Genetic testing revealed a missense variant, CACNA1C-E1115K. The whole-cell patch clamp technique was used to measure CACNA1C-WT and -E1115K currents when heterologously expressed in TSA201 cells. Results: The CACNA1C-E1115K channel exhibited no inward calcium current. Instead, robust cardiac transient outward potassium current (Ito)-like outward currents that were blocked significantly by nifedipine were measured when 2 mM/0.1 mM extracellular/intracellular CaCl2 or 4 mM/141 mM extracellular/intracellular KCl was applied. Furthermore, when 140 mM extracellular NaCl was applied, the CACNA1C-E1115K channel revealed both robust inward persistent Na+ currents with slower inactivation and outward currents, which were also nifedipine sensitive. In contrast, CACNA1C-WT revealed only a small inward persistent Na+ current without a robust outward current. Conclusion: This CACNA1C-E1115K variant destroyed the LTCC's calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward currents and potassium-mediated outward currents. Despite the anticipated 50% reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient's LQTS and arrhythmia phenotype.

AB - Background: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Cav1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC's selectivity filter. Here, we identified and characterized a pore-localizing missense variant, E1115K, that yielded a novel perturbation in the LTCC. Objective: The purpose of this study was to determine whether CACNA1C-E1115K alters the LTCC's selectivity and is the substrate for the patient's LQTS. Methods: The proband was a 14-year-old male with idiopathic QT prolongation and bradycardia. Genetic testing revealed a missense variant, CACNA1C-E1115K. The whole-cell patch clamp technique was used to measure CACNA1C-WT and -E1115K currents when heterologously expressed in TSA201 cells. Results: The CACNA1C-E1115K channel exhibited no inward calcium current. Instead, robust cardiac transient outward potassium current (Ito)-like outward currents that were blocked significantly by nifedipine were measured when 2 mM/0.1 mM extracellular/intracellular CaCl2 or 4 mM/141 mM extracellular/intracellular KCl was applied. Furthermore, when 140 mM extracellular NaCl was applied, the CACNA1C-E1115K channel revealed both robust inward persistent Na+ currents with slower inactivation and outward currents, which were also nifedipine sensitive. In contrast, CACNA1C-WT revealed only a small inward persistent Na+ current without a robust outward current. Conclusion: This CACNA1C-E1115K variant destroyed the LTCC's calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward currents and potassium-mediated outward currents. Despite the anticipated 50% reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient's LQTS and arrhythmia phenotype.

KW - Arrhythmia

KW - CACNA1C

KW - Ion channel

KW - L-type calcium channel

KW - Long QT syndrome

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U2 - 10.1016/j.hrthm.2018.08.030

DO - 10.1016/j.hrthm.2018.08.030

M3 - Article

VL - 16

SP - 270

EP - 278

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

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ER -