A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome

• DOI: 10.1016/j.neuron.2010.04.030
• Publication Date: 2010-06-11T11:03:08Z
• Authors: Barbara Kremeyer; Francisco Lopera; James J. Cox; Aliakmal Momin; Francois Rugiero; Steve Marsh; C. Geoffrey Woods; Nicholas G. Jones; Kathryn J. Paterson; Florence R. Fricker; Andrés Villegas; Natalia Acosta; Nicolás G. Pineda...; Juan Diego Ramírez; Julián Zea; Mari-Wyn Burley; Gabriel Bedoya; David L.H. Bennett; John N. Wood; Andrés Ruiz-Linares
• Keywords: Neuroscience(all); Molecular Sequence Data; HUMDISEASE; 610; Pain; Nerve Tissue Proteins; Syndrome; MOLNEURO; Cell Line; Pedigree; Transient Receptor Potential Channels; SIGNALING; 616; Clinical Study; Humans; Point Mutation; Amino Acid Sequence; Calcium Channels; TRPA1 Cation Channel; Pain Measurement

Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological states.We describe an autosomal-dominant familial episodic syndrome characterized by episodes of debilitating upper body pain, triggered fasting physical stress.Linkage haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12-8q13.Candidate gene sequencing identified point mutation (N855S) in S4 transmembrane segment TRPA1, key sensor for environmental irritants.The mutant channel showed pharmacological profile but altered biophysical properties, with 5-fold increase inward current activation at resting potentials.Quantitative sensory testing demonstrated baseline thresholds enhanced secondary hyperalgesia punctate stimuli treatment mustard oil.TRPA1 antagonists inhibit channel, promising useful therapy disorder.Our findings provide evidence variation TRPA1 can alter perception humans.