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

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; Andres Villegas; Natalia Acosta; Nicolas G. Pineda-Trujillo; Juan Diego Ramirez; Julian Zea; Mari-Wyn Burley; Gabriel Bedoya; David L. H. Bennett; John N. Wood; Andres Ruiz-Linares

doi:10.1016/j.neuron.2010.04.030

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

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, Andres Villegas, Natalia Acosta, Nicolas G. Pineda-Trujillo, Juan Diego Ramirez, Julian Zea, Mari-Wyn Burley, Gabriel Bedoya, David L. H. Bennett, John N. Wood, Andres Ruiz-Linares

Research output: Contribution to journal › Article › peer-review

369 Citations (Scopus)

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.

Original language	English
Pages (from-to)	671 - 680
Number of pages	10
Journal	Neuron
Volume	66
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2010.04.030
Publication status	Published - Jun 2010

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Kremeyer, B., Lopera, F., Cox, J. J., Momin, A., Rugiero, F., Marsh, S., Woods, C. G., Jones, N. G., Paterson, K. J., Fricker, F. R., Villegas, A., Acosta, N., Pineda-Trujillo, N. G., Diego Ramirez, J., Zea, J., Burley, M.-W., Bedoya, G., Bennett, D. L. H., Wood, J. N., & Ruiz-Linares, A. (2010). A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome. Neuron, 66(5), 671 - 680. https://doi.org/10.1016/j.neuron.2010.04.030

@article{4560c34becf342f0bac6dfcdf7dfc21c,

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.",

author = "Barbara Kremeyer and Francisco Lopera and Cox, {James J.} and Aliakmal Momin and Francois Rugiero and Steve Marsh and Woods, {C. Geoffrey} and Jones, {Nicholas G.} and Paterson, {Kathryn J.} and Fricker, {Florence R.} and Andres Villegas and Natalia Acosta and Pineda-Trujillo, {Nicolas G.} and {Diego Ramirez}, Juan and Julian Zea and Mari-Wyn Burley and Gabriel Bedoya and Bennett, {David L. H.} and Wood, {John N.} and Andres Ruiz-Linares",

year = "2010",

month = jun,

doi = "10.1016/j.neuron.2010.04.030",

language = "English",

volume = "66",

pages = "671 -- 680",

journal = "Neuron",

publisher = "CELL PRESS",

number = "5",

}

Kremeyer, B, Lopera, F, Cox, JJ, Momin, A, Rugiero, F, Marsh, S, Woods, CG, Jones, NG, Paterson, KJ, Fricker, FR, Villegas, A, Acosta, N, Pineda-Trujillo, NG, Diego Ramirez, J, Zea, J, Burley, M-W, Bedoya, G, Bennett, DLH, Wood, JN & Ruiz-Linares, A 2010, 'A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome', Neuron, vol. 66, no. 5, pp. 671 - 680. https://doi.org/10.1016/j.neuron.2010.04.030

TY - JOUR

T1 - A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome

AU - Kremeyer, Barbara

AU - Lopera, Francisco

AU - Cox, James J.

AU - Momin, Aliakmal

AU - Rugiero, Francois

AU - Marsh, Steve

AU - Woods, C. Geoffrey

AU - Jones, Nicholas G.

AU - Paterson, Kathryn J.

AU - Fricker, Florence R.

AU - Villegas, Andres

AU - Acosta, Natalia

AU - Pineda-Trujillo, Nicolas G.

AU - Diego Ramirez, Juan

AU - Zea, Julian

AU - Burley, Mari-Wyn

AU - Bedoya, Gabriel

AU - Bennett, David L. H.

AU - Wood, John N.

AU - Ruiz-Linares, Andres

PY - 2010/6

Y1 - 2010/6

N2 - 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.

AB - 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.

U2 - 10.1016/j.neuron.2010.04.030

DO - 10.1016/j.neuron.2010.04.030

M3 - Article

VL - 66

SP - 671

EP - 680

JO - Neuron

JF - Neuron

IS - 5

ER -

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

Abstract

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