Nav1.7-P610T mutation in 2 siblings with persistent ocular pain after corneal axon transection: impaired slow-inactivation and hyperexcitable trigeminal neurons


Journal of Neurophysiology


Mohammad-Reza Ghovanloo, Philip R. Effraim, Jun-Hui Yuan, Betsy R. Schulman, Deborah S. Jacobs, Sulayman D. Dib-Hajj, and Stephen G. Waxman



Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser assisted in situ keratomileusis (LASIK). While most patients do not experience post-operative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons – the ensemble of ion channels and receptors that regulate excitability within these cells -including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons, that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T-Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this pro-excitatory change in channel function, we also demonstrate that this mutation produces hyperexcitability in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons.

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