Pain Mechanisms and Treatments (4)
Pain Management and Treatment (3)
Musculoskeletal pain and rehabilitation (2)
Cardiac electrophysiology and arrhythmias (1)
Ion channel regulation and function (1)
Kist AM, Sagafos D, Rush AM, Neacsu C, Eberhardt E , et al.
PloS one •
Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.
Zhang Z, Schmelz M, Segerdahl M, Quiding H, Centerholt C , et al.
Scandinavian journal of pain •
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.