Dataset Information

Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy.

ABSTRACT: 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 drug-responsive 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.

SUBMITTER: Zhu H

PROVIDER: S-EPMC6957104 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy.

Zhu Haoyue H Zhang Mengqi M Fu Yujiao Y Long Hongyu H Xiao Wenbiao W Feng Li L Xiao Bo B Zhou Luo L

Neuropsychiatric disease and treatment 20200109

<h4>Background and purpose</h4>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 adj ...[more]

PMID: 32021205

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Project description:Epilepsy is one of the most prevalent and drug-refractory neurological disorders. Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and investigate its in epileptogenesis in in vivo and in vitro models through behavioral, electrophysiological, and pathological studies. We used kainic acid- and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons as experimental epileptic models in this study. We first found increased ZDHHC8 expression in the brains of temporal lobe epilepsy (TLE) patients, similar to that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is correlated with human epilepsy. In the in vitro seizure models, knocking down ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and epileptiform-like discharges, while ZDHHC8 overexpression had the opposite effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we observed that ZDHHC8 had a significant modulatory effect on 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further affecting the inward rectification of AMPA currents in acute hippocampal slices in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal surface in the hippocampus, as shown by immunoprecipitation and Western blotting. These results suggest that ZDHHC8 may promote the generation and propagation of seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic effects in drug-resistant epilepsy. Our study provides evidence that may facilitate the development of an alternative approach for the treatment of epilepsy by modulating AMPA/GluA1-mediated neurotransmission.

Dataset Information

Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy.

Publications

Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy.

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