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.

• Authors: Dan Ye, David J Tester, Wei Zhou, John Papagiannis, Michael J Ackerman
• Journal: Heart rhythm (Heart Rhythm) Vol. 16 Issue 2 Pg. 270-278 (02 2019) ISSN: 1556-3871 [Electronic] United States
• PMID: 30172029 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• CACNA1C protein, human
• Calcium Channels, L-Type
• DNA

Topics

• Adolescent
• Autism Spectrum Disorder (genetics, metabolism)
• Bradycardia (diagnosis, genetics, physiopathology)
• Calcium Channels, L-Type (genetics, metabolism)
• Cells, Cultured
• DNA (genetics)
• DNA Mutational Analysis
• Electrocardiography
• Humans
• Male
• Mutation, Missense
• Patch-Clamp Techniques
• Pedigree
• Romano-Ward Syndrome (diagnosis, genetics, physiopathology)