L: +39 0649902037; Fax: +39 064957821; Email: [email protected] These authors contributed equally to this work.# The Author 2014. Published by Oxford University Press.That is an Open Access article distributed below the terms on the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4 .0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original function is adequately cited.Human Molecular Genetics, 2014, Vol. 23, No.also present mood problems and seizures (four 6). Notably, seizure susceptibility linked with cardiac arrhythmia have been described in various K+ channelepsies that may perhaps raise the risk to sudden unexpected death in impacted individuals (7). SQT3s (OMIM 609622) is another cardiac disorder characterized by QT shortening, ventricular tachyarrhythmias and atrial fibrillation that’s brought on by gain-of-function mutations in KCNJ2 (8 ten). The electrophysiological alterations that accompany SQT3S have already been investigated in details demonstrating that gain-of-function mutations in Kir2.1 caused 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 modifications). To date, neither the molecular mechanisms top to channel dysfunction nor the potential 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), as well as 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 role for the inwardly rectifying K+ channels dysfunction in autism pilepsy linked with intellectual disability, which warranted further investigations (11,12). We herein report around the identification of a brand new p.K346T mutation in KCNJ2 in cis with the previously detected p.R18Q variant in KCNJ10 (11). The pathogenic relevance in the mutation was assessed in Xenopus laevis oocytes, HEK293 and glial-like cells. We demonstrated that the K346T mutation causes get of function of your Kir2.1 channels by altering their trafficking and stabilization and suggest that the novel KCNJ2 variant has a combined effect on cardiac rhythm and neuropsychiatric phenotype.RESULTSIdentification of a brand new KCNJ2 mutation in homozygous twins exhibiting SQT3S and autism epilepsy phenotype The clinical case in the two probands has been reported each as SI information and elsewhere (11). In brief, two 9-year-old identical twins (Fig. 1A) displayed epilepsy and severe impairment of social interaction and communication, linked with stereotypes and repetitive behaviors, which were consistent with DSM-IV-TR 85551-10-6 Protocol criteria for ASD. Each children showed an electrocardiogram (ECG) having a markedly short 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 found 53179-13-8 supplier inside the mother nevertheless it was absent in 400 ethnically matched manage chromosomes (Fig. 1A and C) and was not identified in substantial SNP databases (dbSNP and eversusgs.washington.edu/EVS/). Numerous sequence alignment showed that the lysine residue at position 346 (K346) is very conserved in a number of vertebrate species (Fig. 1D) and lies inside the cytoplasmic C-terminus domains of Kir2.1 channel (Fig. 1E).
