Abstract
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.
Highlights
KCNK18 encodes the TWIK-Related Spinal cord K+ channel (TRESK), a member of the two-pore domain (K2P) potassium channel family
Born at term after cesarean delivery, the proband showed a delay in the acquisition of developmental milestones, with the first phonemes at 18 months, walking
To validate the in silico predictions, we examined whether the two missense changes in KCNK18 affect the functional properties of TRESK
Summary
KCNK18 encodes the TWIK-Related Spinal cord K+ channel (TRESK), a member of the two-pore domain (K2P) potassium channel family. Murine TRESK is phosphorylated and maintains an inactive conformation, but, after a calcium signal, the channel is rapidly activated following dephosphorylation by the calcium-dependent phosphatase calcineurin [3,4] To allow this process, calcineurin must bind to the channel through interaction with its non-catalytic sites, helped by the regulatory protein, 14-3-3. The switch between the active and resting states has been intensely investigated [4] and it is mediated by the phosphorylation of TRESK at two different regulatory regions, the 14-3-3 binding site (Serine 252, Ser252, hereafter) and three adjacent serine residues (Ser262, Ser264 and Ser267, collectively named serine cluster, hereafter). We describe the identification of a family with three siblings affected by mild to moderate ID, seizures, and autistic-like behavior with different degrees of severity, carrying biallelic KCNK18 variants, supporting a possible involvement of the gene in neurodevelopmental disorders (NDD)
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