TY - JOUR
T1 - Altered functional properties of a missense variant in the TRESK K+ channel (KCNK18) associated with migraine and intellectual disability
AU - Imbrici, Paola
AU - Nematian-Ardestani, Ehsan
AU - Hasan, Sonia
AU - Pessia, Mauro
AU - Tucker, Stephen J.
AU - D’Adamo, Maria Cristina
N1 - Funding Information:
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).
Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - Calcineurin-dependent regulation
KW - KCNK18 gene missense mutation
KW - TRESK K2P
KW - Two-electrode-voltage-clamp
KW - Xenopus oocytes
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U2 - 10.1007/s00424-020-02382-5
DO - 10.1007/s00424-020-02382-5
M3 - Article
C2 - 32394190
AN - SCOPUS:85084444812
SN - 0031-6768
VL - 472
SP - 923
EP - 930
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
IS - 7
ER -