Abstract 14964: A Novel Caveolin-3 Mutation Identified in a Patient With Profound Drug-Induced QT Prolongation and Sudden Cardiac Arrest Results in Dysfunction of Multiple Ion Channels Responsible for Cardiac Action Potential Duration
Introduction: Caveolin-3 (CAV3) is an essential scaffolding protein for caveolae formation in cardiomyocytes and targets multiple long QT syndrome (LQTS)-associated ion channels including the cardiac sodium channel (Nav1.5, LQT3), L-type calcium channel (Cav1.2, LQT8), and the voltage-gated potassium channels, Kv7.1 (LQT1) and Kv11.1 (LQT2), to the cell surface membrane. Mutations in CAV3 have been linked to LQTS (LQT9) by causing an LQT3-like accentuation in late sodium current. Here, we characterize a novel CAV3-V37L mutation by heterologous co-expression with the 4 major LQTS-related ion channels.
Methods: The proband was a 39-year-old female with drug-induced, in-hospital sudden cardiac arrest (SCA) with documented profound QT prolongation (QTc > 600 ms) and torsades. Her QTc after removal of all offending drugs was 500 ms. LQTS genetic testing revealed a rare CAV3-V37L mutation and the common Kv11.1-K897T polymorphism. The CAV3-V37L and Kv11.1-K897T variants were engineered using site-directed mutagenesis. Standard whole-cell patch clamp technique was used to measure Nav1.5, Cav1.2, Kv7.1, and Kv11.1 currents when heterologously co-expressed with either CAV3-WT or CAV3-V37L in TSA201 cells.
Results: Surprisingly, Nav1.5 channel function was not disrupted by CAV3-V37L. Instead, Cav1.2 channels co-expressed with CAV3-V37L had slower inactivation and a 1.4 fold increase in late current at +10 mV compared to CAV3-WT (p<0.05). Whereas, the Kv7.1 channel exhibited a 75% reduction of peak current density at +80 mV when co-expressed with CAV3-V37L compared to CAV3-WT (p<0.05). Interestingly, when co-expressed with Kv11.1-WT (K897), CAV3-V37L significantly inhibited Kv11.1 peak current density across the voltage from +10 mV to +60 mV (p<0.05 vs. CAV3-WT). However, the Kv11.1-WT (T897) polymorphism rescued the Kv11.1 loss-of-function by CAV3-V37L.
Conclusions: Studies identified the underlying mechanisms of QT prolongation and SCA in a patient with a novel CAV3 mutation. Rather than altered Nav1.5 function, the CAV-V37L mutation precipitated a gain-of-function of Cav1.2 and a loss-of-function of both Kv7.1 and Kv11.1. K897T displayed a modifying effect on the electrophysiological phenotype of Kv11.1 when co-expressed with CAV-V37L.
Author Disclosures: D. Ye: None. W. Zhou: None. D.J. Tester: None. M.J. Ackerman: Consultant/Advisory Board; Modest; Boston Scientific Corp., Gilead Sciences, Inc., Medtronic, Inc., St. Jude Medical. Other; Significant; Transgenomic.
- © 2016 by American Heart Association, Inc.