Hypokalaemic periodic paralysis with a charge-retaining substitution in the voltage sensor

Abstract

Familial hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. HypoPP is characterized by repeated episodes of paralytic attacks with hypokalemia, and several variants in CACNA1S coding for CaV1.1 and SCN4A coding for NaV1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either CaV1.1 or NaV1.4. Mutant channels have aberrant leak currents called “gating pore currents,” and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five HypoPP cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other HypoPP families. One case is R219K in NaV1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in CaV1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of CaV1.1-R897K. NaV1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by NaV1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical HypoPP phenotypes do not fit the canonical view that the essential defect in HypoPP mutant channels is the gating pore current and raise the possibility that HypoPP pathogenesis might be heterogeneous and diverse.

Case Report: A Novel CACNA1S Mutation Associated With Hypokalemic Periodic Paralysis in a Chinese Family

“…However, no frameshift mutation has been reported to be associated with HypoPP. Only a handful of nonsense, frameshift, or splice-site mutations was found in congenital myopathy families (Hunter et al, 2015;Schartner et al, 2017;Kubota et al, 2020). We may detect the first alone frameshift mutation of CACNA1S in HypoPP cases without congenital myopathy phenotype, which may contribute to further understanding the genetic etiology of this disease.…”

Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP

“…This insight directly led to the hypothesis that R/X mutations in HypoPP might also give rise to gating pore currents and that this would produce an anomalous inward current at the resting potential of muscle fibers. This notion was quickly confirmed for HypoPP mutations in Na V 1.4 ( Sokolov et al, 2007 ; Struyk and Cannon, 2007 ) and was subsequently verified for 12 of 13 R/X mutations in Na V 1.4, with the one exception being the only known charge-conserving mutation, R219K ( Kubota et al, 2020 ). Moreover, model simulations show that the small anomalous conductance of the gating pore current (only ∼1% of the total resting conductance in a muscle fiber) is sufficient to cause paradoxical depolarization of the resting potential in low K + ( Jurkat-Rott et al, 2012 ; Struyk and Cannon, 2008 ).…”

Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

“…They are mainly located at the positions within voltage-sensors (e.g., R192Q, R195K, V581L/M, R583Q, K1343Q, R1352Q, R1667W, K1670R), the S4-S5 linkers (e.g., S2181L, C1369Y, L1682P, W1683R) and the cytoplasmic S6 activation gates (e.g., F363S, V714A, D715E, F1506S, I1810L; Figures 3, 4) where other GOF channelopathy mutations are typically located (Eising and van den Maagdenberg, 2017;Tyagi et al, 2020). Moreover, some variants associated with FHM-1 also neutralize S4 gating charges, including positions in which also Cav1.1 and Nav1.4 gating-pores were reported (e.g., R195K, R583Q, K1343Q, R1352Q; asterisks in Figure 4; note that R195K in Cav2.1 and R219K in Nav1.4 are both chargeretaining substitutions; Ducros et al, 2001;Kubota et al, 2020) and may therefore affect neuronal excitability also through gating pore currents (Jurkat-Rott et al, 2012). This hypothesis should be tested experimentally and by molecular modeling like for other Cavs (Monteleone et al, 2017;Flucher, 2020).…”

“…Figure 4 illustrates that outside of Cav1.1 α1, disease-associated mutations were reported in a total of at least 17 S4 gating charges in 5 different Cav isoforms (Cav1.2, Cav1.3, Cav2.1, Cav3.1, Cav3.2). Many of them are located in the same homologous positions as Cav1.1 HypoPP1 mutations or pathogenic Nav1.4 (HypoPP2) or Nav1.5 (arrhythmias and dilatated cardiomyopathy) mutations (indicated by asterisks in Figure 4 ; Groome et al, 2017 ; Jiang D. et al, 2019 ; Kubota et al, 2020 ).…”