Abstract | BACKGROUND: 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.
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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)
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Copyright | Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- NAV1.5 Voltage-Gated Sodium Channel
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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
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