Familial gain-of-function Nav1.9 mutation in a painful channelopathy
| Autor: | Yang Yang, Rene H. M. te Morsche, Sulayman D. Dib-Hajj, Stephen G. Waxman, Joost P.H. Drenth, Juan Politei, Chongyang Han |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Mutation business.industry Mutant medicine.disease_cause medicine.disease Resting potential Nav1.9 03 medical and health sciences Psychiatry and Mental health Electrophysiology Transmembrane domain 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] Dorsal root ganglion Channelopathy medicine Surgery Neurology (clinical) business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neurology, Neurosurgery, and Psychiatry, 88, 233-240 Journal of Neurology, Neurosurgery, and Psychiatry, 88, 3, pp. 233-240 |
| ISSN: | 0022-3050 |
| DOI: | 10.1136/jnnp-2016-313804 |
| Popis: | Item does not contain fulltext OBJECTIVE: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9 channelopathies. METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A. Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses. RESULTS: A novel Nav1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing. CONCLUSIONS: This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Nav1.9, strengthening human validation of this channel as a potential therapeutic target for pain. |
| Databáze: | OpenAIRE |
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