Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC287
Functional characterisation of mutations in the TRESK K2P K+ channel (KCNK18) associated with common migraine.
I. Andres-Enguix1, L. Shang1, P. J. Stansfeld2, M. S. Sansom2, J. Morahan4, R. G. Lafreniere3, G. Rouleau3, M. Cader5, S. J. Tucker1
1. Dept Physics, University of Oxford, Oxford, United Kingdom. 2. Dept Biochemistry, University of Oxford, Oxford, United Kingdom. 3. Medicine, Universit
An inherited mutation in the KCNK18 gene has been shown to be associated with ‘migraine with aura’. This is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. KNCK18 encodes the TWIK-related spinal cord potassium channel (TRESK), a member of the K2P family of potassium channels. In a previous study we have shown that a mutation in KCNK18 (F139WfsX24) segregates perfectly with typical migraine with aura in a large pedigree and functional characterisation of this mutation by expression in Xenopus oocytes demonstrates that it causes a complete loss of TRESK function (1). This identifies a role for TRESK in the pathogenesis of typical migraine with aura and further supports the role of this channel as a potential therapeutic target. In this study we have examined the functional properties of other mutations identified in the human KCNK18 gene and find that whilst some have no obvious effect on channel activity, several variants produce a dramatic loss-of-function phenotype similar to the F139WfsX24 mutation. These results have a major impact on our understanding of how defective TRESK activity may contribute to the pathogenesis of common migraine and the role of common genetic variants in this process.
Where applicable, experiments conform with Society ethical requirements