Familial episodic limb pain in kindreds with novel Nav1.9 mutations

Abstract

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

“…A likely role for Na v 1.9 in the control of normal gut motility, attributable to altered plexus function, seems consistent with the effects of mutation in human carriers and gain of function is associated with constipation (e.g. [69]). With these facts in mind, it may be possible to understand the defects in pain signalling found in humans with rare, heritable mutations in SCN11A.…”

Mechanical allodynia triggered by cold exposure in mice with the Scn11a p.R222S mutation: a novel model of drug therapy for neuropathic pain related to NaV1.9

“…Statistical significance in AUC was calculated by Welch's t test ***p < 0.001, ****p < 0.0001 vs the WT DW group and by one-way ANOVA and post hoc Dunnett's test # p < 0.05, ### p < 0.001 vs the R222S DW group Alismatis rhizome and Dioscoreae rhizome, which are components of GJG, also contribute to improved blood flow through inhibition of platelet aggregation (Suzuki et al 1998a). As demonstrated by previous reports (Okuda et al 2016;Kabata et al 2018), warming of the lesions is effective in relieving pain in patients with familial episodic limb pain. Hence, the multiple mechanisms of GJG, including improvements of peripheral blood flow that contributes to lesion warming, may be involved in the analgesic efficacy of GJG on mechanical allodynia in R222S mice.…”

“…Cold exposure may alter other signaling events in the DRG, such as the overall profile of protein kinase, the specific upregulation of Fyn kinase that regulates Na V 1.7 channels in response to repeated cold stress (Kozaki et al 2015;Li et al 2018), or even other posttranslational modifications, including phosphorylation, that can modify the trafficking and functions of Na V channels in neurons (Laedermann et al 2015). As suggested by previous clinical reports, the relationship of SCN11A gene mutations and environmental changes may be involved in painful disorders (Leipold et al 2013;Zhang et al 2013;Huang et al 2014;Han et al 2015;Woods et al 2015;Okuda et al 2016;Han et al 2017;King et al 2017;Castoro et al 2018;Kabata et al 2018;Huang et al 2019). Clearly, further research, for example with stable Na V 1.9-expressing cell lines, is necessary to clarify the molecular mechanisms of SCN11A gain-offunction mutations.…”

“…Na V 1.9 exhibits slow activation kinetics and plays a role in setting activation thresholds and membrane potentials (Wood et al 2004 ; Bennett et al 2019 ). Several recent studies have revealed that SCN11A mutations are associated with gain-of-function Na V 1.9 phenotypes and are related to peripheral paresthesia, such as painless disorders (Leipold et al 2013 ; Woods et al 2015 ; Phatarakijnirund et al 2016 ; King et al 2017 ), painful small fiber neuropathies (Huang et al 2014; Kleggetveit et al 2016 ; Han et al 2017 ), and familial episodic pain syndromes, including familial episodic limb pain that is clinically indicated as paroxysmal limb pain induced by fatigue, bad weather, or cold temperature during infancy to adolescence (Zhang et al 2013 ; Leipold et al 2015 ; Okuda et al 2016 ; Kabata et al 2018 ).…”

“…Gabapentin, a voltage-gated calcium channel blocker, frequently used for the treatment of neuropathy, failed to control the nociceptive pain of patients with the SCN11A p.R225C mutation (Castoro et al 2018 ). Acetaminophen (AcAP) and cyclooxygenase-2 inhibitors, common analgesic agents, are often prescribed for patients with familial episodic pain syndromes (Okuda et al 2016 ; Kabata et al 2018 ), yet they were also unable to alleviate the pain symptoms. In Japan, goshajinkigan (GJG), a traditional Japanese medicine (Kampo), is prescribed to relieve low back pain, numbness, dysuria, pollakisuria, itch, blurred vision, and neuropathies (Tawata et al 1994 ; Cascella and Muzio 2017 ).…”