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A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura – Source: Nature Medicine, Sep 2010

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[Note: According to one of many articles on this international analysis of genetic data for more than 50,000 people (published Sep 26 by Telegraph.co.uk), the researchers have described this gene, which is associated with regulation of the neurotransmitter glutamate, as acting “like a pain thermostat in the brain” that determines “the threshold at which the body feels pain” and therefore might be dialed down or “switched off” by medication. The suggestion is that the mutation of the gene common in migraine with aura sufferers may play a role in migraine initiation by allowing accumulation of glutamate in nerve cell junctions.]

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms1.

A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia2.

We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.

Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree.

We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion.

Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele.

These results therefore:

• Support a role for TRESK in the pathogenesis of typical migraine with aura,

• And further support the role of this channel as a potential therapeutic target.

Source: Nature Medicine, Sep 26, 2010; 16, pp. 1157-1160. DOI:10.1038/nm.2216, by Lafrenière RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenière F, McLaughlan S, Dubé MP, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G, Rouleau GA. Centre of Excellence in Neuromics and Department of Medicine, Université de Montréal; Centre Hospitalier de l'Université de Montréal, Research Centre; Notre-Dame Hospital, Montreal; Emerillon Therapeutics, Montreal, Quebec, Canada.

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