| Abstract | Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy. |
| Authors | Caroline R Fertleman, Mark D Baker, Keith A Parker, Sarah Moffatt, Frances V Elmslie, Bjarke Abrahamsen, Johan Ostman, Norbert Klugbauer, John N Wood, R Mark Gardiner, Michele Rees
(Affiliation: Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, 5 University Street, London WC1E 6JJ, United Kingdom.)
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| Journal | Neuron
(Neuron)
Vol. 52
Issue 5
Pg. 767-74
(Dec 7 2006)
ISSN: 0896-6273 United States |
| PMID | 17145499
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Analgesics, Non-Narcotic
- SCN9A protein, human
- Sodium Channel Blockers
- Sodium Channels
- Carbamazepine
|
| Topics |
- Alleles
- Amino Acid Sequence
- Analgesics, Non-Narcotic
(pharmacology)
- Carbamazepine
(pharmacology)
- Cell Line
- Chromosome Mapping
- Cloning, Molecular
- DNA Mutational Analysis
- Electrophysiology
- Genotype
- Humans
- Linkage (Genetics)
(physiology)
- Molecular Sequence Data
- Mutation
(physiology)
- Neuralgia
(genetics, physiopathology)
- Patch-Clamp Techniques
- Pedigree
- Phenotype
- Sodium Channel Blockers
- Sodium Channels
(drug effects, genetics, physiology)
- Transfection
- Variation (Genetics)
|
