Contribution of <i>KCNJ10</i> Gene Polymorphisms in Childhood Epilepsy

Dai, Alper; Akcali, Aylin; Koska, Safinur; Öztuzcu, Serdar; Cengiz, Beyhan; Demiryürek, Abdullah Tuncay

doi:10.1177/0883073814539560

Cited by 16 publications

(13 citation statements)

References 23 publications

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“…Although oK ir 4.1cKO mice did not exhibit alterations in the structure of myelin or progressive disability, these animals died much earlier than control littermates ( Figure 5A ). K ir 4.1 is a risk factor gene for epilepsy ( Bockenhauer et al, 2009 ; Dai et al, 2015 ; Inyushin et al, 2010 ; Lenzen et al, 2005 ; Scholl et al, 2009 ), raising the possibility that K ir 4.1 dysfunction in oligodendrocytes is sufficient to increase seizure susceptibility and induce death. Consistent with this hypothesis, oK ir 4.1cKO mice exhibited occasional seizures and mice that had died were often discovered with limbs extended, suggesting that they had suffered a catastrophic seizure.…”

Section: Resultsmentioning

confidence: 99%

“…Several spontaneously arising rodent models of epilepsy were found to have altered K ir 4.1 levels ( Harada et al, 2013 ; Nagao et al, 2013 ), and a single-nucleotide polymorphism in the K ir 4.1 gene ( kcnj10 ) was found to be responsible for differences in seizure susceptibility between C57BL6 and DBA/2 mice ( Ferraro et al, 2004 ; Inyushin et al, 2010 ). In addition, polymorphisms in KCNJ10 are risk factors for epilepsy in humans ( Buono et al, 2004 ; Dai et al, 2015 ; Guo et al, 2015 ; Lenzen et al, 2005 ), and seizures are a prominent component of the human disorder SeSAME/EAST syndrome, which results from loss-of-function mutations in KCNJ10 ( Bockenhauer et al, 2009 ; Scholl et al, 2009 ). It has been assumed that the seizures are primarily caused by astrocyte abnormalities and downstream sequelae.…”

Section: Discussionmentioning

confidence: 99%

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Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility

Larson

Mironova

Vanderpool

et al. 2018

eLife

128

147

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The inwardly rectifying K+ channel Kir4.1 is broadly expressed by CNS glia and deficits in Kir4.1 lead to seizures and myelin vacuolization. However, the role of oligodendrocyte Kir4.1 channels in controlling myelination and K+ clearance in white matter has not been defined. Here, we show that selective deletion of Kir4.1 from oligodendrocyte progenitors (OPCs) or mature oligodendrocytes did not impair their development or disrupt the structure of myelin. However, mice lacking oligodendrocyte Kir4.1 channels exhibited profound functional impairments, including slower clearance of extracellular K+ and delayed recovery of axons from repetitive stimulation in white matter, as well as spontaneous seizures, a lower seizure threshold, and activity-dependent motor deficits. These results indicate that Kir4.1 channels in oligodendrocytes play an important role in extracellular K+ homeostasis in white matter, and that selective loss of this channel from oligodendrocytes is sufficient to impair K+ clearance and promote seizures.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility

Larson

Mironova

Vanderpool

et al. 2018

eLife

128

147

View full text Add to dashboard Cite

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“…Recent studies showed that loss-of-function mutations of the human gene ( KCNJ10 ) encoding Kir4.1 channels are responsible for the SeSAME/EAST syndrome, an autosomal recessive disorder characterized by seizures, sensorineural deafness, ataxia, intellectual disability and electrolyte imbalance (Bockenhauer et al, 2009; Scholl et al, 2009; Reichold et al, 2010). Genetic variations of KCNJ10 have also been related to epilepsy (Buono et al, 2004; Ferraro et al, 2004; Lenzen et al, 2005; Dai et al, 2015), a group of neurological diseases characterized by seizure disorders. Other diseases associated to Kir4.1 channels include spinocerebellar ataxia (Gilliam et al, 2014), autism (Sicca et al, 2011), Alzheimer disease (Wilcock et al, 2009), and Huntington disease (Tong et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Kir4.1 potassium channels by quinacrine

et al. 2017

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Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Particularly, Kir4.1 channels are involved in the astroglial spatial potassium buffering. In this work, we examined the effects of the cationic amphiphilic drug quinacrine on Kir4.1 channels heterologously expressed in HEK293 cells, employing the patch clamp technique. Quinacrine inhibited the currents of Kir4.1 channels in a concentration and voltage dependent manner. In inside-out patches, quinacrine inhibited Kir4.1 channels with an IC50 value of 1.8 ± 0.3 μM and with extremely slow blocking and unblocking kinetics. Molecular modeling combined with mutagenesis studies suggested that quinacrine blocks Kir4.1 by plugging the central cavity of the channels, stabilized by the residues E158 and T128. Overall, this study shows that quinacrine blocks Kir4.1 channels, which would be expected to impact the potassium transport in several tissues.

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“…28 Meanwhile, in a pediatric epilepsy patients group in Japan, the GT genotype of KCNJ10 gene rs2486253 polymorphism also significantly increased the risk for development of idiopathic generalized epilepsy of children. 29 Among a Chinese Han population, Hapmap database shows that rs1130183 are all CC genotypes, with extremely low frequency of T allele, which is not suitable for our SNPs study. Previously, rs6690889 TC and TT genotypes were found to have lower frequencies in genetic generalized epilepsy patients than in healthy controls recruited from southern China by the research of Guo et al Hence, they speculated that potential SNP loci of KCNJ10 may contribute to seizure susceptibility and antiepileptic drug resistance.…”

Section: Discussionmentioning

confidence: 99%

<p>Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy</p>

Zhu¹,

Zhang²,

Fu³

et al. 2020

NDT

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Background and Purpose: Epilepsy is a common chronic neurological disorder. About one third of epilepsy patients will suffer from drug resistance after rational selection of antiepileptic drug treatment. The formation of drug-resistant epilepsy has quite a few causes of which genetic factors are considered to be the most important. Previous studies have suggested that the aquaporin 4(AQP4) and inward rectifier potassium ion channel Kir4.1 (encoded by gene KCNJ10) may act in concert to adjust water homeostasis and concentration of potassium ions in extracellular spaces of the central nervous system. Therefore, these two molecules would play a major role in the regulation of the excitability of neurons. In order to explore the potential mechanism of genetic factors related to AQP4 and Kir4.1, we conducted a study to analyze the effects of the AQP4 and KCNJ10 genes' single nucleotide polymorphisms (SNPs) on epileptic drug resistance and seizure susceptibility in a group of Chinese Han patients with focal epilepsy. Materials and Methods: In total, 510 patients with focal-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tag SNPs was based on the Hapmap database and Haploview software. Genotyping of three loci of the AQP4 gene (rs1058424, rs3763043 and rs35931) and nine loci of the KCNJ10 gene (rs12122979, rs1186685, rs6690889, rs2486253, rs1186675, rs12402969, rs12729701, rs1890532 and rs3795339) was conducted on the Sequenom MassARRAY iPLEX platform. Results: The distribution of genotype and allele frequencies of selected SNP loci of AQP4 and KCNJ10 genes showed no significant difference between the drug-resistant and drugresponsive groups (p>0.05), and no significant difference between all the idiopathic focal epilepsy patients and healthy controls either. Conclusion: AQP4 and KCNJ10 genetic polymorphisms may not be associated with drug resistance or seizure susceptibility of focal epilepsy in the Chinese Han population.

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Contribution of KCNJ10 Gene Polymorphisms in Childhood Epilepsy

Cited by 16 publications

References 23 publications

Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility

Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility

Inhibition of Kir4.1 potassium channels by quinacrine

<p>Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy</p>

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