p.L1612P, a Novel Voltage-gated Sodium Channel Nav1.7 Mutation Inducing a Cold Sensitive Paroxysmal Extreme Pain Disorder

Abstract

Background: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. Methods: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. Results: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady–state inactivation curve (V1/2 from −61.8 ± 4.5 mV to −30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady–state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. Conclusions: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.

Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy

“…For example, Peddareddygari LR et al demonstrated that homozygous p.G2755T mutation in exon 15 of this gene is associated with congenital insensitivity to pain (CIP) [26, 27]. Other authors have related some mutations like p.L1612P with a Cold Sensitive Paroxysmal Extreme Pain Disorder [28]. According to these data and the role of this gene in pain and cold perception, we decided to analyzed SCN9A missense SNPs (rs6746030 (p.R1150W), rs74401238 (p.R1110Q) and rs41268673 (p.P610T)) as a potential cause of genetic susceptibility for a cold-induced neuropathy like OXLIN.…”

Small‐fiber neuropathy: Expanding the clinical pain universe

“…PEPD is caused by gain‐of‐function Na V 1.7 variants that mostly result in impaired fast inactivation. So far, 10 variants in Na V 1.7 are known that cause PEPD . It is thought that the variant induces a depolarizing shift of steady‐state fast inactivation, hampering channel closure during action potential electrogenesis.…”

“…So far, 10 variants in Na V 1.7 are known that cause PEPD. [206][207][208][209][210][211][212] It is thought that the variant induces a depolarizing shift of steadystate fast inactivation, hampering channel closure during action potential electrogenesis.…”

Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

“…The V1309D, V1309F, and V1310F mutations are located in the S4-S5 linker region of domain III and they have been shown to cause moderate destabilization of fast inactivation (Jarecki et al, 2008). The G1618R mutation, located within the S4 segment of domain IV, impairs inactivation and retains a persistent current compared to the wild-type (WT) channel (Choi et al, 2011), while another domain IV S4 segment mutation, L1623P, significantly increases ramp current and shortens recovery time from inactivation (Suter et al, 2015). Moreover, electrophysiology study showed that M1638K mutation (within the S5 segment of domain IV) generates faster recovery from inactivation than the WT channel, producing greater currents and reducing the threshold with increased number of action potentials (Fertleman et al, 2006; Dib-Hajj et al, 2008).…”