title: A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.
abstract: Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12-8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans.
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kremeyer
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: Aliakmal
authors.initials: A
authors.lastname: Momin
authors.forename: Francois
authors.initials: F
authors.lastname: Rugiero
authors.forename: Steve
authors.initials: S
authors.lastname: Marsh
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Jones
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Paterson
authors.forename: Florence R
authors.initials: FR
authors.lastname: Fricker
authors.forename: Andrés
authors.initials: A
authors.lastname: Villegas
authors.forename: Natalia
authors.initials: N
authors.lastname: Acosta
authors.forename: Nicolás G
authors.initials: NG
authors.lastname: Pineda-Trujillo
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Ramírez
authors.forename: Julián
authors.initials: J
authors.lastname: Zea
authors.forename: Mari-Wyn
authors.initials: MW
authors.lastname: Burley
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bedoya
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Andrés
authors.initials: A
authors.lastname: Ruiz-Linares
mesh_terms: D000595:Amino Acid Sequence; D015220:Calcium Channels / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010146:Pain / Q000235:genetics* / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D013577:Syndrome; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics*
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels