SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.
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.
Fertleman
Caroline R
CR
Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, 5 University Street, London WC1E 6JJ, United Kingdom.
Baker
Mark D
MD
Parker
Keith A
KA
Moffatt
Sarah
S
Elmslie
Frances V
FV
Abrahamsen
Bjarke
B
Ostman
Johan
J
Klugbauer
Norbert
N
Wood
John N
JN
Gardiner
R Mark
RM
Rees
Michele
M
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
D018712:Analgesics, Non-Narcotic; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002220:Carbamazepine