L: +39 0649902037; Fax: +39 064957821; E-mail: [email protected] These authors contributed equally to this operate.# The Author 2014. Published by Oxford University Press.This can be an Open Access post distributed below the terms on the Inventive Commons Attribution License (http://creativecommons.org/licenses/by/4 .0/), which permits unrestricted reuse, distribution, and reproduction in any medium, supplied the original operate is effectively cited.Human Molecular Genetics, 2014, Vol. 23, No.also present mood disorders and seizures (four six). 1047953-91-2 Purity & Documentation Notably, seizure susceptibility connected with cardiac arrhythmia have already been described in various K+ channelepsies that may possibly raise the risk to sudden unexpected death in impacted sufferers (7). SQT3s (OMIM 609622) is yet another cardiac disorder characterized by QT shortening, ventricular tachyarrhythmias and atrial fibrillation that’s triggered by gain-of-function mutations in KCNJ2 (8 10). The electrophysiological alterations that accompany SQT3S happen to be investigated in particulars demonstrating that gain-of-function mutations in Kir2.1 brought on an increase within the amplitude of either the inward-current (which include for the D172N variant) or outward-current (for instance for the E299V and M301K adjustments). To date, neither the molecular mechanisms top to channel dysfunction nor the prospective consequence on other organs expressing the channel, like the brain, are known. We not too long ago reported on two homozygous twins manifesting intellectual disability, autism spectrum disorder (ASD), and a history of infantile spasms where we detected gain-of-function mutations in KCNJ10, encoding the Kir4.1 channel (11). Those findings highlighted an emerging function for the inwardly rectifying K+ Triallate Technical Information channels dysfunction in autism pilepsy related with intellectual disability, which warranted additional investigations (11,12). We herein report on the identification of a new p.K346T mutation in KCNJ2 in cis using the previously detected p.R18Q variant in KCNJ10 (11). The pathogenic relevance on the mutation was assessed in Xenopus laevis oocytes, HEK293 and glial-like cells. We demonstrated that the K346T mutation causes obtain of function of the Kir2.1 channels by altering their trafficking and stabilization and suggest that the novel KCNJ2 variant includes a combined effect on cardiac rhythm and neuropsychiatric phenotype.RESULTSIdentification of a new KCNJ2 mutation in homozygous twins exhibiting SQT3S and autism epilepsy phenotype The clinical case in the two probands has been reported both 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, linked with stereotypes and repetitive behaviors, which were constant with DSM-IV-TR criteria for ASD. Each youngsters showed an electrocardiogram (ECG) with a markedly brief repolarization time and conspicuously narrow and 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 identified inside the mother nevertheless it was absent in 400 ethnically matched handle chromosomes (Fig. 1A and C) and was not located in big SNP databases (dbSNP and eversusgs.washington.edu/EVS/). A number of sequence alignment showed that the lysine residue at position 346 (K346) is extremely conserved in several vertebrate species (Fig. 1D) and lies inside the cytoplasmic C-terminus domains of Kir2.1 channel (Fig. 1E).
