Table 3.
Disease-related mutations in Nav1.4 and Nav1.5 that enhance closed-state inactivation.
| Gene Protein | Location | Mutation | Defective inactivation | Phenotype | References |
|---|---|---|---|---|---|
|
SCN4A Nav1.4 |
DⅢS4 (R3) | R1135C* (rat R1128C) |
Delayed fast inactivation, hyperpolarizing shift in SSA, delayed recovery from inactivation, enhanced CSI, delayed recovery from CSI |
hypoPP | Groome et al. 2014 [60] Groome et al. 2014 [61] |
| DⅢS4 (R3) | R1135H* (rat R1128H) |
Delayed fast inactivation, hyperpolarizing shift in SSA, delayed recovery from inactivation, enhanced CSI, delayed recovery from CSI |
hypoPP | Groome et al. 2014 [60] | |
| DIVS4 (R2) | R1451L | Delayed fast inactivation, hyperpolarizing shift in SSA, accelerated recovery from inactivation, enhanced CSI, accelerated entry into CSI |
hypoPP and myotonia (homozygous) hyperPP and myotonia (heterozygous) |
Luo et al. 2018 [26] | |
|
SCN5A Nav1.5 |
DⅡ-DⅢ linker | E1053K | Accelerated fast inactivation, delayed recovery from inactivation, enhanced intermediate inactivation, enhanced CSI |
BrS | Mohler et al. 2004 [66] |
| DⅢ-DIV linker | Delta KPQ | Delayed fast inactivation, enhanced CSI, accelerated entry into CSI |
LQTS | Viswanathan et al. 2001 [63] Chen et al. 2002 [64] |
|
| DIVS1 | N1541D | Delayed fast inactivation, hyperpolarizing shift in SSA, delayed recovery from inactivation, enhanced CSI, accelerated entry into CSI |
BrS, SSS, SVT |
Dharmawan et al. 2019 [57] | |
| DIVS4 (R4) | R1632C | Hyperpolarizing shift in SSA, delayed recovery from inactivation, profound use-dependent current attenuation, enhanced CSI, accelerated entry into CSI, delayed recovery from CSI |
BrS, SSS, SVT |
Nakajima et al. 2005 [34] Dharmawan et al. 2019 [57] |
|
| C-terminus | 1795insD | Delayed fast inactivation, delayed recovery from inactivation, profound use-dependent current attenuation, hyperpolarizing shift in SSA, enhanced slow inactivation, enhanced CSI, accelerated entry into CSI |
LQTS, BrS |
Veldkamp et al. 2000 [67] Viswanathan et al. 2001 [63] |
|
| C-terminus | L1825P | Delayed fast inactivation, hyperpolarizing shift in SSA enhanced CSI, accelerated entry into CSI |
LQTS | Makita et al. 2002 [65] |
BrS, Brugada syndrome; CSI, closed-state inactivation; HyperPP, hyperkalemic periodic paralysis; HypoPP, hypokalemic periodic paralysis; LQTS, long QT syndrome; R2-4, second to fourth arginine residues (R2, R3, and R4) in domain IV-segment 4; SSA, steady-state availability; SSS, sick sinus syndrome; SVT, supraventricular tachyarrhythmia. *, Electrophysiological data were obtained from rat Nav1.4 R1128C or rat Nav1.4 R1128H. Descriptions of closed-state inactivation are written in bold and italic.