Paroxysmal Extreme Pain Disorder M1627K Mutation in Human Na_v1.7 Renders DRG Neurons Hyperexcitable

Abstract

BackgroundParoxysmal extreme pain disorder (PEPD) is an autosomal dominant painful neuropathy with many, but not all, cases linked to gain-of-function mutations in SCN9A which encodes voltage-gated sodium channel Nav1.7. Severe pain episodes and skin flushing start in infancy and are induced by perianal probing or bowl movement, and pain progresses to ocular and mandibular areas with age. Carbamazepine has been effective in relieving symptoms, while other drugs including other anti-epileptics are less effective.ResultsSequencing of SCN9A coding exons from an English patient, diagnosed with PEPD, has identified a methionine 1627 to lysine (M1627K) substitution in the linker joining segments S4 and S5 in domain IV. We confirm that M1627K depolarizes the voltage-dependence of fast-inactivation without substantially altering activation or slow-inactivation, and inactivates from the open state with slower kinetics. We show here that M1627K does not alter development of closed-state inactivation, and that M1627K channels recover from fast-inactivation faster than wild type channels, and produce larger currents in response to a slow ramp stimulus. Using current-clamp recordings, we also show that the M1627K mutant channel reduces the threshold for single action potentials in DRG neurons and increases the number of action potentials in response to graded stimuli.ConclusionM1627K mutation was previously identified in a sporadic case of PEPD from France, and we now report it in an English family. We confirm the initial characterization of mutant M1627K effect on fast-inactivation of Nav1.7 and extend the analysis to other gating properties of the channel. We also show that M1627K mutant channels render DRG neurons hyperexcitable. Our new data provide a link between altered channel biophysics and pain in PEPD patients.

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

“…Altered expression of VGSCs that are found in primary sensory neurons, e.g. NaV1.3, NaV1.7, NaV1.8, and NaV1.9, has been shown to associate at various degrees with human neuropathies (12)(13)(14)(15)(16)(17) and animal neuropathy models (18 -21). Among the peripheral VGSC isoforms, NaV1.8 is the predominant tetrodotoxin-resistant sodium channel expressed exclusively in primary sensory neurons with particularly high levels of expression in nociceptive neurons of small-and medium-sized soma diameters (22).…”

A Novel SCN9A Gene Mutation in a Patient with Carbamazepine-ResistantParoxysmal Extreme Pain Disorder

“…Met1627Lys mutation has been previously described in a sporadic case of paroxysmal extreme pain disorder from France [1], and then reported in an English family [2]. In both families, carbamazepine was effective with low-doses in two adult women (200 to 600 mg/d) reducing the frequency of attacks to just one a year.…”

“…The (adult) patients with the M1627K mutation were carbamazepine-responsive with 600 mg/d, whereas a dose of 400 mg/d in a two-year-old boy weighing 8 kg merely halved the frequency of the pain attacks to one every two days. A number of voltage-clamp studies have shown that the M1627K mutation has a marked effect on fast inactivation of NaV1.7 [1][2][3] and resurgent sodium currents [3]. However none of these electrophysiological studies assessed the effect of carbamazepine in the M1627K mutant.…”

“…The SIFT, PolyPhen-2, MutationTaster and Align GVGD prediction tools all suggested that Met1627Arg was likely to affect protein function. Lastly, another mutation of the same amino acid (Met1627Lys) has been reported in carbamazepine-responsive paroxysmal extreme pain disorder [2,3].…”

Prolonged Sinus Pauses Revealing A Paroxysmal Extreme Pain Disorder: Is It A Frequent Situation? A Case Report

“…The universe of painful Na-channelopathies -human disorders caused by mutations in voltage-gated sodium channels -has recently expanded in three dimensions. We now know that mutations of sodium channels cause not only rare genetic 'model disorders' such as inherited erythromelalgia and channelopathy-associated insensitivity to pain but also common painful neuropathies.The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system [2]. The voltage-gated sodium ion channel Nav 1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav 1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes.…”