KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Alleles*; Intellectual Disability/*genetics ; Mutation/*genetics ; Neurodevelopmental Disorders/*genetics ; Potassium Channels/*genetics; Adolescent ; Adult ; Amino Acid Sequence ; Animals ; Base Sequence ; Calcineurin/metabolism ; Female ; Genome, Human ; Humans ; Ion Channel Gating/drug effects ; Ionomycin/pharmacology ; Male ; Pedigree ; Potassium Channels/chemistry ; Siblings ; Xenopus laevis/metabolism ; Young Adult

The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18 , and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease.

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D15D18000410001 Ministero dell'Istruzione, dell'Università e della Ricerca; MH111661 United States MH NIMH NIH HHS; I20LU08 Research Innovation and Development Trust, University of Malta; BooKind E20LG42 Research Innovation and Development Trust, University of Malta; 31M452 United Arab Emirates University; 31M468 United Arab Emirates University; 12M020 United Arab Emirates University

Keywords: ASD; K2P; KCNK18; TRESK; autism spectrum disorder; intellectual disability; potassium channel

0 (KCNK18 protein, human)
0 (Potassium Channels)
56092-81-0 (Ionomycin)
EC 3.1.3.16 (Calcineurin)

Date Created: 20210702 Date Completed: 20210715 Latest Revision: 20210715

20221213

PMC8200030

10.3390/ijms22116064

34199759