Functional Investigation of a GRIN2A Variant Associated with Rolandic Epilepsy.
10.1007/s12264-017-0182-6
- Author:
Xing-Xing XU
1
;
Xiao-Rong LIU
2
;
Cui-Ying FAN
1
;
Jin-Xing LAI
2
;
Yi-Wu SHI
2
;
Wei YANG
1
;
Tao SU
2
;
Jun-Yu XU
1
;
Jian-Hong LUO
3
;
Wei-Ping LIAO
4
Author Information
1. Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, 310058, China.
2. Institute of Neuroscience, Department of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, 510260, China.
3. Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, 310058, China. luojianhong@zju.edu.cn.
4. Institute of Neuroscience, Department of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, 510260, China. wpliao@tom.com.
- Publication Type:Case Reports
- Keywords:
Epilepsy;
GRIN2A;
Mutation;
NMDA receptors
- MeSH:
Adolescent;
Epilepsy, Rolandic;
genetics;
Humans;
Male;
Mutation;
Receptors, N-Methyl-D-Aspartate;
genetics
- From:Neuroscience Bulletin
2018;34(2):237-246
- CountryChina
- Language:English
-
Abstract:
N-methyl-D-aspartate receptors (NMDARs), a subtype of glutamate-gated ion channels, play a central role in epileptogenesis. Recent studies have identified an increasing number of GRIN2A (a gene encoding the NMDAR GluN2A subunit) mutations in patients with epilepsy. Phenotypes of GRIN2A mutations include epilepsy-aphasia disorders and other epileptic encephalopathies, which pose challenges in clinical treatment. Here we identified a heterozygous GRIN2A mutation (c.1341T>A, p.N447K) from a boy with Rolandic epilepsy by whole-exome sequencing. The patient became seizure-free with a combination of valproate and lamotrigine. Functional investigation was carried out using recombinant NMDARs containing a GluN2A-N447K mutant that is located in the ligand-binding domain of the GluN2A subunit. Whole-cell current recordings in HEK 293T cells revealed that the N447K mutation increased the NMDAR current density by ~1.2-fold, enhanced the glutamate potency by 2-fold, and reduced the sensitivity to Mg inhibition. These results indicated that N447K is a gain-of-function mutation. Interestingly, alternative substitutions by alanine and glutamic acid at the same residue (N447A and N447E) did not change NMDAR function, suggesting a residual dependence of this mutation in altering NMDAR function. Taken together, this study identified human GluN2A N447K as a novel mutation associated with epilepsy and validated its functional consequences in vitro. Identification of this mutation is also helpful for advancing our understanding of the role of NMDARs in epilepsy and provides new insights for precision therapeutics in epilepsy.
