Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome.

Abstract

BACKGROUND:

Mutations in SCN5A, which encodes the cardiac voltage-gated sodium channels, can be associated with multiple electrophysiological phenotypes. A novel SCN5A R1632C mutation, located in the domain IV-segment 4 voltage sensor, was identified in a young male patient who had a syncopal episode during exercise and presented with atrial tachycardia, sinus node dysfunction, and Brugada syndrome.

OBJECTIVE:

We sought to elucidate the functional consequences of the R1632C mutation.

METHODS:

The wild-type (WT) or R1632C SCN5A mutation was coexpressed with β1 subunit in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp methods.

RESULTS:

INa density, measured at -20 mV from a holding potential of -120 mV, for R1632C was significantly lower than that for WT (R1632C: -433 ± 52 pA/pF, n = 14; WT: -672 ± 90 pA/pF, n = 15; P < .05); however, no significant changes were observed in the steady-state activation and fast inactivation rate. The steady-state inactivation curve for R1632C was remarkably shifted to hyperpolarizing potentials compared with that for WT (R1632C: V1/2 = -110.7 ± 0.8 mV, n = 16; WT: V1/2 = -85.9 ± 2.5 mV, n = 17; P < .01). The steady-state fast inactivation curve for R1632C was also shifted to the same degree. Recovery from fast inactivation after a 20-ms depolarizing pulse for R1632C was remarkably delayed compared with that for WT (R1632C: τ = 246.7 ± 14.3 ms, n = 8; WT: τ = 3.7 ± 0.3 ms, n = 8; P < .01). Repetitive depolarizing pulses at various cycle lengths greatly attenuated INa for R1632C than that for WT.

CONCLUSION:

R1632C showed a loss of function of INa by an enhanced fast-inactivated state stability because of a pronounced impairment of recovery from fast inactivation, which may explain the phenotypic manifestation observed in our patient.

• Authors: Tadashi Nakajima, Yoshiaki Kaneko, Akihiro Saito, Masaki Ota, Takafumi Iijima, Masahiko Kurabayashi
• Journal: Heart rhythm (Heart Rhythm) Vol. 12 Issue 11 Pg. 2296-304 (Nov 2015) ISSN: 1556-3871 [Electronic] United States
• PMID: 26031372 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• NAV1.5 Voltage-Gated Sodium Channel

Topics

• Adolescent
• Brugada Syndrome (diagnosis, genetics)
• Cardiac Electrophysiology
• DNA Mutational Analysis
• Electrocardiography (methods)
• Genetic Predisposition to Disease
• Humans
• Male
• Mutation, Missense
• NAV1.5 Voltage-Gated Sodium Channel (genetics)
• Patch-Clamp Techniques
• Phenotype
• Polymerase Chain Reaction (methods)
• Prognosis
• Rare Diseases
• Severity of Illness Index