• Heart Rhythm · Nov 2015

    Case Reports

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

    • Tadashi Nakajima, Yoshiaki Kaneko, Akihiro Saito, Masaki Ota, Takafumi Iijima, and Masahiko Kurabayashi.
    • Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan. Electronic address: tnakajim@gunma-u.ac.jp.
    • Heart Rhythm. 2015 Nov 1; 12 (11): 2296-304.

    BackgroundMutations 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.ObjectiveWe sought to elucidate the functional consequences of the R1632C mutation.MethodsThe 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.ResultsINa 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.ConclusionR1632C 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.Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

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