title: SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.
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.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.
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Fertleman
authors.forename: Mark D
authors.initials: MD
authors.lastname: Baker
authors.forename: Keith A
authors.initials: KA
authors.lastname: Parker
authors.forename: Sarah
authors.initials: S
authors.lastname: Moffatt
authors.forename: Frances V
authors.initials: FV
authors.lastname: Elmslie
authors.forename: Bjarke
authors.initials: B
authors.lastname: Abrahamsen
authors.forename: Johan
authors.initials: J
authors.lastname: Ostman
authors.forename: Norbert
authors.initials: N
authors.lastname: Klugbauer
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: R Mark
authors.initials: RM
authors.lastname: Gardiner
authors.forename: Michele
authors.initials: M
authors.lastname: Rees
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology; D002460:Cell Line; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D008040:Genetic Linkage / Q000502:physiology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000235:genetics* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D014162:Transfection
chemical_list: D018712:Analgesics, Non-Narcotic; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002220:Carbamazepine