SRR intronic variation inhibits expression of its neighbouring
SMG6 gene and protects against temporal lobe epilepsy
a, b, #
, Xu Zhou
, Qian Xie
, Zhonghua Ma
, Fuhai Sun
, Lili Cui
, Yujie Cai
, Jiawu Fu
, Zhou Liu
, You Li
, Haihong Zhou
, Jianghao Zhao
, Yanyan Chen
, Ying Chen
, Jun Chen
, Wei Qi
, Chaowen Sun
, Bin Zhao
*, Keshen Li
Department of Neurology, Afﬁliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
Guangdong Key Laboratory of Age-related Cardiac and Cerebral Diseases, Guangdong Medical University, Zhanjiang,
Clinical Research Center, Guangdong Medical University, Zhanjiang, Guangdong, China
Emergency Department, Afﬁliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Department of Neurology, the First People’s Hospital of Pingdingshan, Pingdingshan, Hebei, China
Department of Neurology, Central People’s Hospital of Zhanjiang, Zhanjiang, Guangdong, China
Institute of Neurology, Guangdong Medical University, Zhanjiang, Guangdong, China
Stroke Center, Neurology& Neurosurgery Division, Clinical Medicine Research Institute & the First Afﬁliated Hospital, Jinan
University, Guangzhou, Guangdong, China
Received: August 10, 2017; Accepted: October 30, 2017
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 signiﬁ-
cantly 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 inhi-
bits 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.
temporal lobe epilepsy
According to the World Health Organization, approximately 50 million
people live with epilepsy worldwide, and nearly, one-third of these
individuals are severely affected by intractable seizures. Notably, an
increasing amount of evidence indicates that temporal lobe epilepsy
(TLE), the most common partial epilepsy, is a primary origin of
intractable seizures, but progress in its clinical treatments has always
These three authors contributed equally to this work.
*Correspondence to: Bin ZHAO, Prof.
Keshen LI, Ph.D.
ª 2018 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1883-1893