Inherited Erythromelalgia (IEM) causes debilitating neuropathic pain characterized by burning combined with redness in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) on the other hand, differs in its clinical picture as it affects proximal body areas like rectal, ocular or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. While hyperexcitability of IEM mutations is caused by a hyperpolarizing shift of activation, allowing Nav1.7 to open at lower potentials, PEPD mutations induce a depolarizing shift of steady-state fast inactivation, hampering channel closure during an action potential.

Here we characterize a new mutation of Nav1.7, A1632T, found in a patient presenting IEM symptoms, using whole-cell voltage-clamp recordings of transfected HEK cells. Surprisingly, channel activation is unaltered by this mutation, but steady-state fast inactivation was shifted to more depolarized potentials, a characteristic normally caused by PEPD mutations. Previously an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD (Estacion et al. 2008) was reported.

In order to assess the structural implications of amino acid substitutions in A1632, we generated a 3D homology model of Nav1.7 based on the recently published crystal structure of the sodium channel NavAb. We identified a possible negatively-charged causative for the mutation-induced gating shifts, which we investigated by substituting A at position 1632 with D/E/K/T/V.

The gain-of-function mutations of Nav1.7 cause remarkable changes in the channel's biophysical properties and may help to identify new structural motifs that impact the equilibrium of functional states of the channel.