Altered functional properties of a missense variant in the TRESK K+ channel (KCNK18) associated with migraine and intellectual disability

Journal article

Mutations in the KCNK18 gene that encodes the TRESK K2P potassium channel have previously been linked with typical familial migraine with aura. Recently, an atypical clinical case has been reported in which a male individual carrying the p.Trp101Arg (W101R) missense mutation in the KCNK18 gene was diagnosed with intellectual disability and migraine with brainstem aura. Here we report the functional characterization of this new missense variant. This mutation is located in a highly conserved residue close to the selectivity filter, and our results show although these mutant channels retain their K+ selectivity and calcineurin-dependent regulation, the variant causes an overall dramatic loss of TRESK channel function as well as an initial dominant-negative effect when co-expressed with wild-type channels in Xenopus laevis oocytes. The dramatic functional consequences of this mutation thereby support a potentially pathogenic role for this variant and provide further insight into the relationship between the structure and function of this ion channel.

Authors: Imbrici, P; Nematian-Ardestani, E; Hasan, S; Pessia, M; Tucker, SJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: Pflugers Archiv : European Journal of Physiology
• Volume: 472
• Issue: 7
• Pages: 923-930
• Place of publication: Germany
• Publication date: 2020-05-12
• Acceptance date: 2020-04-22
• DOI: 10.1007/s00424-020-02382-5
• EISSN: 1432-2013
• ISSN: 0031-6768
• Pmid: 32394190
• Language: English
• Keywords: KCNK18 gene missense mutation; calcineurin-dependent regulation; Xenopus oocytes; TRESK K2P; two-electrode-voltage-clamp; FFR