A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura

Abstract

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

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…two-pore domain potassium channel (K2P), encoded by KCNK18, was recently reported (Lafreniere et al 2010).…”

“…By screening the KCNK18 gene in a large multigenerational family with typical migraine with aura, inherited in a dominant fashion, Lafreniere et al (2010) identified a mutation in TRESK (F139WfsX24). They also identified prominent TRESK expression in migraine salient areas such as the trigeminal ganglion.…”

Migraine: Molecular Basis and Herbal Medicine

“…Some mutations that were found to be related with hemiplegic migraine (de Vries et al, 2006(de Vries et al, , 2009, and common migraine (Lafrenière et al, 2010), are good examples of mutation biomarkers. Some polymorphisms were also found to be more valuable for screening patients with higher susceptibility into migraine attack in the future (De Vries et al, 2006).…”

“…Like other complex genetic traits, finding responsible genes are much more difficult (de Vries et al, 2006). Despite these problems and absence of any evidence of association between genes encoding the ion channels and common migraine in previous studies (Nyholt et al, 2008), it has been reported recently that there is a strong genetic link to common forms of migraine (Lafrenière et al, 2010). Using a candidate gene approach and functional analysis, researchers have identified a mutation, F139wfsX24, in the gene encoding the two-pore domain potassium channel TRESK (TWIK-related spinal cord potassium channel) KCNK18 in the patients with migraine with aura.…”

“…The TRESK is involved in pain pathways and regulates neuronal excitability. The mutation can lead to a complete loss of channel function (Lafrenière et al, 2010) and for the first time, a common form of migraine is linked to a genetic mutation (Wood, 2010). The agonist-promoted upregulation of TRESK activity can act as a beneficial treatment option, either as an acute therapy or as a long-term preventive approach for individuals with migraine (Lafrenière et al, 2010).…”