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

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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.

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Acknowledgments

We gratefully acknowledge the financial support of the University of Malta Research, Innovation and Development Trust (RIDT), the Biotechnology and Biological Sciences Research Council (BBSRC), and United Arab Emirates University (Grants n. 31M452 and 31M468).

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Author notes

  1. Paola Imbrici and Ehsan Nematian-Ardestani contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, Bari, Italy

    Paola Imbrici

  2. Department of Physiology & Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD, Msida, 2080, Malta

    Ehsan Nematian-Ardestani, Mauro Pessia & Maria Cristina D’Adamo

  3. Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait

    Sonia Hasan

  4. Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

    Mauro Pessia

  5. Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, UK

    Stephen J. Tucker

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  1. Paola Imbrici
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  2. Ehsan Nematian-Ardestani
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  3. Sonia Hasan
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  4. Mauro Pessia
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  5. Stephen J. Tucker
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  6. Maria Cristina D’Adamo
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Contributions

PI designed the study, analyzed data, and wrote the paper; ENA performed electrophysiological experiments and analyzed data; SH critically discussed the results and reviewed the literature; SJT and MP critically revised the manuscript and supervised the work; MCD designed the study, supervised the work and wrote the manuscript.

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Correspondence to Maria Cristina D’Adamo.

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The authors have nothing to disclose. No competing financial interests exist.

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This article is part of the special issue on Channelopathies: from mutation to diseases in Pflügers Archiv—European Journal of Physiology

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Imbrici, P., Nematian-Ardestani, E., Hasan, S. et al. Altered functional properties of a missense variant in the TRESK K+ channel (KCNK18) associated with migraine and intellectual disability. Pflugers Arch - Eur J Physiol 472, 923–930 (2020). https://doi.org/10.1007/s00424-020-02382-5

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