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

Paola Imbrici, Ehsan Nematian-Ardestani, Sonia Hasan, Mauro Pessia, Stephen J. Tucker, Maria Cristina D’Adamo

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)923-930
Number of pages8
JournalPflugers Archiv European Journal of Physiology
Volume472
Issue number7
DOIs
Publication statusPublished - Jul 1 2020

Keywords

  • Calcineurin-dependent regulation
  • KCNK18 gene missense mutation
  • TRESK K2P
  • Two-electrode-voltage-clamp
  • Xenopus oocytes

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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