Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Center for Molecular Medicine Cologne, Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
Int J Mol Sci. 2021 Jun 4;22(11):6064. doi: 10.3390/ijms22116064.
The TWIK-related spinal cord potassium channel (TRESK) is encoded by , 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 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.
TWIK 相关的脊髓钾通道（TRESK）由 编码，该基因的变异先前与家族性伴先兆偏头痛易感性（MIM #613656）相关。同一蛋白中的单个氨基酸替换，p.Trp101Arg，也与智力障碍（ID）相关，这使得该基因的变异可能与不同的疾病有关。在这里，我们报道了在一个家族中鉴定出两种等位基因错义变异（p.Tyr163Asp 和 p.Ser252Leu），该家族的三个兄弟姐妹受轻度至中度 ID、自闭症谱系障碍（ASD）和其他神经发育相关特征的影响。对变异体单独或组合进行的功能特征分析显示，通道活性受损。有趣的是，Ser252 是 TRESK 的一个重要调节位点，这表明该残基的改变可能导致下游的附加效应。这些突变的功能相关性以及在家族中所有受影响成员中的观察到的共分离现象，扩展了与改变的 TRESK 功能相关的临床变异性，并进一步深入了解这种离子通道功能改变与人类疾病之间的关系。
