Hypokalaemic periodic paralysis and myotonia in a patient with homozygous mutation p.R1451L in NaV1.4

Abstract

Dominantly inherited channelopathies of the skeletal muscle voltage-gated sodium channel NaV1.4 include hypokalaemic and hyperkalaemic periodic paralysis (hypoPP and hyperPP) and myotonia. HyperPP and myotonia are caused by NaV1.4 channel overactivity and overlap clinically. Instead, hypoPP is caused by gating pore currents through the voltage sensing domains (VSDs) of NaV1.4 and seldom co-exists clinically with myotonia. Recessive loss-of-function NaV1.4 mutations have been described in congenital myopathy and myasthenic syndromes. We report two families with the NaV1.4 mutation p.R1451L, located in VSD-IV. Heterozygous carriers in both families manifest with myotonia and/or hyperPP. In contrast, a homozygous case presents with both hypoPP and myotonia, but unlike carriers of recessive NaV1.4 mutations does not manifest symptoms of myopathy or myasthenia. Functional analysis revealed reduced current density and enhanced closed state inactivation of the mutant channel, but no evidence for gating pore currents. The rate of recovery from inactivation was hastened, explaining the myotonia in p.R1451L carriers and the absence of myasthenic presentations in the homozygous proband. Our data suggest that recessive loss-of-function NaV1.4 variants can present with hypoPP without congenital myopathy or myasthenia and that myotonia can present even in carriers of homozygous NaV1.4 loss-of-function mutations.

Role of the voltage sensor module in Nav domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

“…Intriguingly, structural studies demonstrated that R1451 (R2) in Na v 1.4 DIVS4 coupled with E1373 ( Figure 1), one of the residues of pGCTC, in DIVS1, and that R1451L disrupted its electrostatic interaction with E1373 [9,14,26]. Luo et al hypothesized that the R1451L mutation may destabilize the S4 movement that should be immobilized and allow for a quicker recovery of the S4 to the hyperpolarized/resting state, which may lead to an accelerated recovery from inactivation [26]. This concept may be supported by the fact that neutralizing or charged-reversing mutations of E1373 also accelerate the recovery from inactivation [15].…”

“…Functional studies of R1 mutations, including R1448S, R1448H, R1448P and R1448C, associated with PC, commonly exhibited a delayed fast inactivation and hyperpolarizing shift in steady-state availability, with either a delayed or accelerated recovery from inactivation [18][19][20][21][22][23][24]. R2 mutations, including R1451C and R1451L, associated with PC (with or without hyperPP or hypoPP), also exhibited a delayed fast inactivation and hyperpolarizing shift in steady-state availability [25,26]. Contrary to the report of R1451L by Poulin et al [25], Luo et al reported that a homozygous R1451L carrier showed hypoPP and myotonia, whereas heterozygous R1451L carriers showed hyperPP and myotonia, and R1451L displayed an accelerated recovery from inactivation [26].…”

“…R2 mutations, including R1451C and R1451L, associated with PC (with or without hyperPP or hypoPP), also exhibited a delayed fast inactivation and hyperpolarizing shift in steady-state availability [25,26]. Contrary to the report of R1451L by Poulin et al [25], Luo et al reported that a homozygous R1451L carrier showed hypoPP and myotonia, whereas heterozygous R1451L carriers showed hyperPP and myotonia, and R1451L displayed an accelerated recovery from inactivation [26]. Intriguingly, they also reported that R1451L displayed an enhanced CSI.…”

“…Regarding CSI, the R1451L enhanced and accelerated entry into CSI. However, recovery from CSI has not been evaluated [26].…”

“…Taken together with the results of structure-function studies, these CSI alterations of R1128C (R3) and R1128H (R3) mutations in rat Na v 1.4 DⅢS4 may be caused by an impaired DⅢS4 movement through disrupted native electrostatic interactions of DⅢS4 and pGCTC in DⅢS2 [60,61]. In contrast, R1451L (R2) in Na v 1.4 DIVS4 displayed an enhanced and accelerated entry into CSI (Table 3), possibly by an impaired DIVS4 movement through disrupted interactions of R1451L and a residue (E1373) of pGCTC in DIVS1 [26], consistent with the notion that neutralization of arginines in Na v 1.4 DIVS4 enhances CSI [62], although recovery from CSI of R1451L has not been examined. These findings suggested the involvement of coupling of DⅢS4 or DIVS4 with each pGCTC in CSI in native Na v 1.4, and may support the notion that, during subthreshold depolarization, outward movement across the membrane and subsequent immobilization of DⅢS4 and DIVS4 of native Na v 1.4 drives entry into CSI, and its remobilization drives recovery from CSI during repolarization [2].…”