title: A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia.
abstract: Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated CNS and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain, and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in NaV1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglion (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel NaV1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function NaV1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN.
authors: Department of Neurology.|Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510.|Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516.
authors: Brian S
authors: BS
authors: Tanaka
authors: Department of Neurology.|Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510.|Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516.
authors: Peng
authors: P
authors: Zhao
authors: Department of Neurology.|Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510.|Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516.
authors: Fadia B
authors: FB
authors: Dib-Hajj
authors: Convergence Pharmaceuticals Ltd, a Biogen company, Cambridge, United Kingdom.
authors: Valerie
authors: V
authors: Morisset
authors: Convergence Pharmaceuticals Ltd, a Biogen company, Cambridge, United Kingdom.
authors: Simon
authors: S
authors: Tate
authors: Department of Neurology.|Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510.|Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516.
authors: Stephen G
authors: SG
authors: Waxman
authors: Department of Neurology.|Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510.|Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516.
authors: Sulayman D
authors: SD
authors: Dib-Hajj
keywords: Nav1.6; chronic pain; resurgent current; trigeminal neuralgia; voltage-gated sodium channel