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SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.

ABSTRACT: D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genotyped for three SRR tag single nucleotide polymorphisms. The frequencies of the GG genotype at rs4523957 T > G were reduced in the TLE cases in the initial cohort (cohort 1) and were confirmed in the independent cohort (cohort 2). An analysis of all TLE cases in cohort 1 + 2 revealed that the seizure frequency and drug-resistant incidence were significantly decreased in carriers of the GG genotype at rs4523957. Intriguingly, the activity of the SMG6 promoter with the mutant allele at rs4523957 decreased by 22% in the dual-luciferase assay, and up-regulated expression of SMG6 was observed in an epilepsy rat model. This study provides the first demonstration that the GG genotype is a protective marker against TLE. In particular, variation at rs4523957 likely inhibits SMG6 transcription and plays a key role against susceptibility to and severity of TLE. The significance of SMG6 hyperfunction in epileptic seizures deserves to be investigated in future studies.

SUBMITTER: Tao H

PROVIDER: S-EPMC5824374 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.

Tao Hua H Zhou Xu X Xie Qian Q Ma Zhonghua Z Sun Fuhai F Cui Lili L Cai Yujie Y Ma Guoda G Fu Jiawu J Liu Zhou Z Li You Y Zhou Haihong H Zhao Jianghao J Chen Yanyan Y Mai Hui H Chen Ying Y Chen Jun J Qi Wei W Sun Chaowen C Zhao Bin B Li Keshen K

Journal of cellular and molecular medicine 20180124 3

D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genoty ...[more]

PMID: 29363864

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Project description:ObjectiveTo identity phenotypes of self-reported symptoms of psychopathology and their correlates in patients with temporal lobe epilepsy (TLE).Method96 patients with TLE and 82 controls were administered the Symptom Checklist 90-Revised (SCL-90-R) to characterize emotional-behavioral status. The nine symptom scales of the SCL-90-R were analyzed by unsupervised machine learning techniques to identify latent TLE groups. Identified clusters were contrasted to controls to characterize their association with sociodemographic, clinical epilepsy, neuropsychological, psychiatric, and neuroimaging factors.ResultsTLE patients as a group exhibited significantly higher (abnormal) scores across all SCL-90-R scales compared to controls. However, cluster analysis identified three latent groups: (1) unimpaired with no scale elevations compared to controls (Cluster 1, 42% of TLE patients), (2) mild-to-moderate symptomatology characterized by significant elevations across several SCL-90-R scales compared to controls (Cluster 2, 35% of TLE patients), and (3) marked symptomatology with significant elevations across all scales compared to controls and the other TLE phenotype groups (Cluster 3, 23% of TLE patients). There were significant associations between cluster membership and demographic (education), clinical epilepsy (perceived seizure severity, bitemporal lobe seizure onset), and neuropsychological status (intelligence, memory, executive function), but with minimal structural neuroimaging correlates. Concurrent validity of the behavioral phenotype grouping was demonstrated through association with psychiatric (current and lifetime-to-date DSM IV Axis 1 disorders and current treatment) and quality-of-life variables.SignificanceSymptoms of psychopathology in patients with TLE are characterized by a series of discrete phenotypes with accompanying sociodemographic, cognitive, and clinical correlates. Similar to cognition in TLE, machine learning approaches suggest a developing taxonomy of the comorbidities of epilepsy.

Dataset Information

SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.

Publications

SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.

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