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

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

Spoiler: Authors

Kremeyer, Barbara; Lopera, Francisco; Cox, James J.; Momin, Aliakmal; Rugiero, Francois; Marsh, Steve; Woods, C. Geoffrey; Jones, Nicholas G.; Paterson, Kathryn J.; Fricker, Florence R.; Villegas, Andrés; Acosta, Natalia; Pineda-Trujillo, Nicolás G.; Ramírez, Juan Diego; Zea, Julián; Burley, Mari-Wyn; Bedoya, Gabriel; Bennett, David L.H.; Wood, John N.; Ruiz-Linares, Andrés

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.

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This paper (Kremeyer et al.) says:

Transient receptor potential (TRP) channels are cation channels that are implicated in all aspects of sensation, including vision, olfaction, mechanosensation, thermosensation, and damage sensing.

I was reading about TRP channels after they were mentioned in the Peripheral neurons, CRH, and sickness behavior thread.

This paper interested me because it connects a specific change in one ion channel with a kind of complicated pain phenotype:

Individuals with [the pain phenotype] present with episodes of debilitating upper body pain starting in infancy that are usually triggered by fasting or fatigue (illness, cold temperature, and physical exertion being contributory factors). Triggers did not start attacks with 100% reliability and often a combination of factors are needed; a typical example would be swimming in cold water not having eaten for a number of hours. These episodes have a typical duration of ∼1.5 hr, starting with a prodromal phase (which can sometimes be aborted, mainly by resting and eating), followed by intense pain, and terminating in a period of exhaustion and deep sleep.

Not only is the trigger confusing, the actual attack sounds like a bunch of stuff happening at once (and awful, feel bad for this family):

The period of intense pain is accompanied by breathing difficulties, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall. Affected individuals reported no altered pain sensitivity outside the episodes. They had a normal neurological examination, including normal sensitivity to light touch, pin prick, vibration sense, and joint position sense.

It seems informative that a single mutation can lead to such a complicated attack occurring under certain conditions, and yet a normal phenotype the rest of the time.

 

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The phenotype was found in one family, where it was being passed on as a dominant Mendelian trait, and the researchers identified the specific point mutation causing it.

This change was observed in all affected individuals but not in unaffected family members. Sequencing of 139 ethnically matched unaffected controls failed to detect the c.A2564G mutation in the general population.

The mutation was to a environmental irritant-sensing ion channel, TRPA1, located in sensory nerves. They then created the ion channels in vivo (both with and without the mutation) and figured out what was different about it. The upshot (assuming my understanding is correct) was that it sends too strong a signal, but only under particular conditions:

Biophysical studies using heterologously expressed channels show that the N855S mutation does not alter exogenous or endogenous ligand binding, but does increase current flow through the activated channel at negative membrane potentials.

As to how this might lead to the overall phenotype, they suggest:

The initial trigger for TRPA1 activation is unknown, but the contribution of tiredness, cold, and fasting to the attacks, coupled with the preventive role of food and warming, suggests that some metabolic dysfunction, for example, lowered membrane potentials or increased intracellular calcium levels, could contribute to the start of attacks