Exonic mutations in SCN9A (Na_V1.7) are found in a minority of patients with erythromelalgia

Abstract

Background and aim "Gain-of-function" mutations in voltage-gated sodium channel NaV1.7 have been linked to erythromelalgia (EM), characterized by painful hot and red hands and feet. We investigated the proportion of patients with EM that carry a mutation in NaV1.7 or in other pain-related genes and studied possible clinical differences. Methods In this study, 48 patients with EM were screened for mutations in a total of 29 candidate genes, including all sodium channel subunits, transient receptor potential channels (TRPA1, TRPV1, TRPM8), neurotrophic factors (NGF, NGFR, BDNF, GDNF, NTRK1 and WNK1) and other known pain-related genes (CACNG2, KCNS1, COMT, P2RX3, TAC1, TACR1), using a combination of next generation sequencing and classical Sanger sequencing. Results In 7/48 patients protein-modifying mutations of NaV1.7 (P187L, I228M, I848T (n = 4) and N1245S) were identified. Patients with the I848T mutation could be identified clinically based on early onset and severity of the disease. In contrast, there were no clinical characteristics that differentiated the other patients with NaV1.7 mutation from those patients without. We also found more than twenty rare protein-modifying genetic variants in the genes coding for sodium channels (NaV1.8, NaV1.9, NaV1.6, NaV1.5, NaV2.1, SCN1B, SCN3B), transient receptor potential channel (TRPA1, TRPV1), and other pain-related targets (WNK1 and NGFR). Conclusion We conclude that functionally characterized mutations of NaV1.7 (I848T) are present only in a minority of patient with EM. Albeit the majority of patients (27/48) carried rare protein-modifying mutations the vast majority of those will most probably not be causally linked to their disease. Implications The key question remaining to be solved is the possible role of rare variants of NaV1.8, NaV1.9, or beta-subunits in provoking chronic pain conditions or even EM.

SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing

“…We describe here a 53 year old woman with symptoms beginning at the age of 35 for whom genetic testing revealed the heterozygous amino acid substitution M650K, Methionine (M) to Lysine (K), in her SCN10A gene encoding for Nav1.8 [8]. No additional mutation was identified in her other sodium channel or candidate genes.…”

“…Genetic testing was performed as previously described [8] and showed a heterozygous single-point mutation in SCN10A which was not found in 96 controls (it is also listed as very rare in the ExAC browser: http://exac.broadinstitute.org/variant/3-38783939-A-T). The study was approved by the regional ethical committee REK (Regional Committees for Medical and Health and Health ethics) South East, record-number S-07204a.…”

“…Often, comparatively few abnormalities are described during the relatively pain free intervals and these abnormalities are often compatible with a small fiber neuropathy (SFN), such as elevated thermal thresholds indicating hypofunction or fiber degeneration [6–8]. In a previous microneurography study analyzing patients with EM, spontaneous activity in C-nociceptors and mechanically sensitized C-fibers were described [5,9].…”

“…: [24–28]). Recently, rare variants of genes other than SCN9a were described in patients with clinically verified erythromelalgia: those genes included SCN10A (Nav1.8), SCN11A (Nav1.9), SCN5A (Nav1.5), SCN7A (Nav2.1), SCN8A (Nav1.6), SCN1B (Nav β1 subunit), SCN3B (Nav β3 subunit), TRPA1, TRPV1, WNK1 and NGFR [8]. …”

“…Here we provide a detailed description of the p.M650K mutation of the TTXr Nav1.8 [8] through its clinical phenotype, microneurography findings, voltage-clamp and current-clamp analysis, offering insights into the role of Nav1.8 in ADS and the generation of peripheral pain in an erythromelalgia patient.…”