Pavinato, Lisa ORCID: 0000-0002-7630-8365, Nematian-Ardestani, Ehsan, Zonta, Andrea, De Rubeis, Silvia, Buxbaum, Joseph, Mancini, Cecilia, Bruselles, Alessandro ORCID: 0000-0002-1556-4998, Tartaglia, Marco, Pessia, Mauro ORCID: 0000-0002-2857-6795, Tucker, Stephen J., D'Adamo, Maria Cristina ORCID: 0000-0002-6758-6064 and Brusco, Alfredo (2021). KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity. Int. J. Mol. Sci., 22 (11). BASEL: MDPI. ISSN 1422-0067

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pavinato, LisaUNSPECIFIEDorcid.org/0000-0002-7630-8365UNSPECIFIED
Nematian-Ardestani, EhsanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zonta, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Rubeis, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buxbaum, JosephUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mancini, CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruselles, AlessandroUNSPECIFIEDorcid.org/0000-0002-1556-4998UNSPECIFIED
Tartaglia, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pessia, MauroUNSPECIFIEDorcid.org/0000-0002-2857-6795UNSPECIFIED
Tucker, Stephen J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
D'Adamo, Maria CristinaUNSPECIFIEDorcid.org/0000-0002-6758-6064UNSPECIFIED
Brusco, AlfredoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-599116
DOI: 10.3390/ijms22116064
Journal or Publication Title: Int. J. Mol. Sci.
Volume: 22
Number: 11
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1422-0067
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CALCIUM-DEPENDENT ACTIVATION; POTASSIUM CHANNEL; K+ CHANNEL; GENETIC-VARIANTS; DOCKING SITE; MUTATIONS; MIGRAINE; PHOSPHORYLATION; POLYMORPHISMS; CALCINEURINMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59911

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