L: +39 0649902037; Fax: +39 064957821; E-mail: [email protected] These authors contributed equally to this perform.# The Author 2014. Published by Oxford University Press.This really is an Open Access article distributed beneath the terms of the Inventive Commons Attribution License (http://creativecommons.org/licenses/by/4 .0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original operate is appropriately cited.Human Molecular Genetics, 2014, Vol. 23, No.also present mood issues and seizures (4 six). Notably, seizure susceptibility connected with cardiac arrhythmia have already been described in quite a few K+ channelepsies that may raise the danger to sudden unexpected death in impacted individuals (7). SQT3s (OMIM 609622) is an additional cardiac disorder characterized by QT shortening, ventricular tachyarrhythmias and atrial fibrillation that is triggered by gain-of-function mutations in KCNJ2 (8 10). The electrophysiological alterations that accompany SQT3S have already been investigated in details demonstrating that gain-of-function mutations in Kir2.1 brought on an increase in the amplitude of either the inward-current (for instance for the D172N variant) or outward-current (for example for the E299V and M301K changes). To date, neither the molecular mechanisms top to channel dysfunction nor the prospective consequence on other organs expressing the channel, including the brain, are recognized. We not too long ago reported on two homozygous twins manifesting intellectual disability, autism spectrum disorder (ASD), and also a history of infantile spasms exactly where we detected gain-of-function mutations in KCNJ10, encoding the Kir4.1 channel (11). Those findings highlighted an emerging role for the inwardly rectifying K+ channels dysfunction in autism pilepsy associated with intellectual disability, which warranted additional investigations (11,12). We herein Tetrahydrothiophen-3-one custom synthesis report on the identification of a new p.K346T mutation in KCNJ2 in cis with all the previously detected p.R18Q variant in KCNJ10 (11). The pathogenic relevance of the mutation was assessed in Xenopus laevis oocytes, HEK293 and glial-like cells. We demonstrated that the K346T mutation causes obtain of function on the Kir2.1 channels by altering their trafficking and stabilization and recommend that the novel KCNJ2 variant includes a combined impact on cardiac rhythm and neuropsychiatric phenotype.RESULTSIdentification of a new KCNJ2 mutation in homozygous twins exhibiting SQT3S and autism epilepsy phenotype The clinical case on the two probands has been reported each as SI information and elsewhere (11). In short, two 9-year-old identical twins (Fig. 1A) displayed epilepsy and extreme impairment of social interaction and communication, related with stereotypes and repetitive behaviors, which have been consistent with DSM-IV-TR criteria for ASD. Both young children showed an electrocardiogram (ECG) using a markedly brief repolarization time and conspicuously narrow and CASIN site peaked T waves (QTc interval, 331 ms) (Fig. 1B). A novel heterozygous KCNJ2 variant (c.1037A.C, p.K346T) was identified, by direct gene sequencing (Fig. 1C). The mutation was also found in the mother but it was absent in 400 ethnically matched control chromosomes (Fig. 1A and C) and was not discovered in large SNP databases (dbSNP and eversusgs.washington.edu/EVS/). Various sequence alignment showed that the lysine residue at position 346 (K346) is highly conserved in various vertebrate species (Fig. 1D) and lies inside the cytoplasmic C-terminus domains of Kir2.1 channel (Fig. 1E).