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

Heart Rhythm : the Official Journal of the Heart Rhythm Society
Dan YeMichael J Ackerman

Abstract

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. 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. 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. 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...Continue Reading

Citations

Mar 13, 2020·Circulation Journal : Official Journal of the Japanese Circulation Society·Megumi FukuyamaMinoru Horie
Apr 22, 2020·Circulation·Ange MaguyJin Li
Jul 19, 2019·Journal of Clinical Medicine·Oscar CampuzanoRamon Brugada
Mar 3, 2020·Frontiers in Molecular Neuroscience·Sidharth TyagiRoger A Bannister
Nov 15, 2018·Frontiers in Physiology·Shanna Hamilton, Dmitry Terentyev
May 16, 2019·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·Babken Asatryan, Argelia Medeiros-Domingo
Jun 2, 2020·Frontiers in Pharmacology·Arpad Tosaki
Jun 4, 2021·Frontiers in Pediatrics·Rosemary BauerAndy Golden

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