Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy
| Autor: | Sulayman D. Dib-Hajj, Janneke G. J. Hoeijmakers, Shujun Liu, Chongyang Han, Giuseppe Lauria, Ingemar S. J. Merkies, Rene H. M. te Morsche, Catharina G. Faber, Monique M. Gerrits, Stephen G. Waxman, Joost P.H. Drenth |
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| Přispěvatelé: | Gastroenterology & Hepatology, Neurology, Promovendi MHN, Klinische Neurowetenschappen, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, RS: GROW - School for Oncology and Reproduction |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Superior cervical ganglion Genotype Sensory system Superior Cervical Ganglion Polyneuropathies Young Adult Dorsal root ganglion Gene Frequency current-clamp Ganglia Spinal Medicine Humans pain Molecular gastro-enterology and hepatology Membrane transport and intracellular motility [IGMD 2] voltage-clamp Alleles Aged Neurons business.industry Sodium channel NAV1.7 Voltage-Gated Sodium Channel Genetic Variation Middle Aged Sympathetic ganglion Autonomic nervous system medicine.anatomical_structure Autonomic Nervous System Diseases Peripheral nervous system Neuropathic pain Neuralgia Female Neurology (clinical) sense organs Molecular gastro-enterology and hepatology Translational research [IGMD 2] business Neuroscience sodium channel |
| Zdroj: | Brain, 135, 2613-28 Brain, 135, Pt 9, pp. 2613-28 Brain, 135, 2613-2628. Oxford University Press |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | Item does not contain fulltext Patients with small fibre neuropathy typically manifest pain in distal extremities and severe autonomic dysfunction. However, occasionally patients present with minimal autonomic symptoms. The basis for this phenotypic difference is not understood. Sodium channel Na(v)1.7, encoded by the SCN9A gene, is preferentially expressed in the peripheral nervous system within sensory dorsal root ganglion and sympathetic ganglion neurons and their small diameter peripheral axons. We recently reported missense substitutions in SCN9A that encode functional Na(v)1.7 variants in 28% of patients with biopsy-confirmed small fibre neuropathy. Two patients with biopsy-confirmed small fibre neuropathy manifested minimal autonomic dysfunction unlike the other six patients in this series, and both of these patients carry the Na(v)1.7/R185H variant, presenting the opportunity to compare variants associated with extreme ends of a spectrum from minimal to severe autonomic dysfunction. Herein, we show by voltage-clamp that R185H variant channels enhance resurgent currents within dorsal root ganglion neurons and show by current-clamp that R185H renders dorsal root ganglion neurons hyperexcitable. We also show that in contrast, R185H variant channels do not produce detectable changes when studied by voltage-clamp within sympathetic neurons of the superior cervical ganglion, and have no effect on the excitability of these cells. As a comparator, we studied the Na(v)1.7 variant I739V, identified in three patients with small fibre neuropathy characterized by severe autonomic dysfunction as well as neuropathic pain, and show that this variant impairs channel slow inactivation within both dorsal root ganglion and superior cervical ganglion neurons, and renders dorsal root ganglion neurons hyperexcitable and superior cervical ganglion neurons hypoexcitable. Thus, we show that R185H, from patients with minimal autonomic dysfunction, does not produce detectable changes in the properties of sympathetic ganglion neurons, while I739V, from patients with severe autonomic dysfunction, has a profound effect on excitability of sympathetic ganglion neurons. |
| Databáze: | OpenAIRE |
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