According to Goldilocks, just right lies between too little and too much. The same principle can be applied to pain. People with too little pain sensation often injure themselves, but too much pain can be debilitating. Now researchers identify mutations in the same gene that associate with too little and too much pain sensation in recent articles in Nature and Neuron.
Nociceptive neurons of the dorsal root ganglion (DRG) express several different sodium channels. The voltage-gated sodium channel Nav1.7, encoded by SCN9A, is enriched in DRG neurons and helps sum the activity of other sodium channels to generate action potentials, which cause pain sensation.
Cox et al. identified SCN9A mutations in people in a northern Pakistani clan who cannot sense pain, but have normal nerve conduction and temperature and pressure sensation. By positional cloning, the authors identified an 11.7 Mb region on chromosome 2 shared in all affected individuals in three related families. Finer mapping failed to show a single haplotype in affected individuals, suggesting that several mutations resulted in the same phenotype. The authors sequenced SCN9A, the best candidate gene as shown by bioinformatic analysis, and found discrete mutations in each family. All of the mutations were 'nonsense' mutations that resulted in early translation termination, presumably truncating Nav1.7.
Each SCN9A mutation rendered Nav1.7 nonfunctional. Cells transfected with the mutated forms of Nav1.7 had normal resting currents, but unlike cells transfected with wild-type Nav1.7, did not respond to depolarization. These data suggest that action potentials that communicate pain information are not generated in affected individuals.
Fertleman et al. identified SCN9A by positional cloning and haplotype analysis as the gene involved in paroxysmal extreme pain disorder (PEPD), which causes burning pain in ocular, mandibular and rectal regions. In eight of the thirteen families examined, affected individuals were heterozygous for one of eight SCN9A mutations. All of the mutations were 'missense' mutations, replacing one amino acid for another, and were located in the inactivation domain or regions that interact with the inactivation domain of Nav1.7.
Cells expressing Nav1.7 mutants had prolonged sodium currents relative to cells expressing wild-type Nav1.7, suggesting persistent activity of DRG neurons in people with PEPD. However, carbamazepine, an anti-epileptic drug that is effective in some people with PEPD, reduced persistent current in cells expressing a Nav1.7 mutant, suggesting that it relieves PEPD by restoring Nav1.7 inactivation.
According to Cox et al., SCN9A polymorphisms may cause population-wide variations in pain threshold. Because people with nonfunctional Nav1.7 lacked pain sensation but were otherwise normal, Nav1.7 inhibitors might relieve pain without causing side effects.