Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Henan Engineering Research Center of Childhood Neurodevelopment, Zhengzhou 450018, Henan, China.
Department of Neurology, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, Henan, China.
Neuroscience. 2023 Aug 21;526:107-120. doi: 10.1016/j.neuroscience.2023.06.018. Epub 2023 Jun 28.
Epilepsy, a neurological condition, is widely prevalent among individuals with intellectual disability (ID). It is well established that N-methyl-D-aspartate (NMDA) receptors play an important role in both epilepsy and ID. Autosomal dominant mutations in the GRIN2B gene, which encodes the GluN2B subunit of the NMDA receptor, have been reported to be associated with epilepsy and ID. However, the underlying mechanism of this association is not well-understood. In this study, we identified a novel GRIN2B mutation (c.3272A > C, p.K1091T) in a patient with epilepsy and ID. The proband was a one year and ten months old girl. GRIN2B variant was inherited from her mother. We further investigated the functional consequences of this mutation. Our findings revealed that the p.K1091T mutation created a Casein kinase 2 phosphorylation site. Using recombinant NMDA receptors containing the GluN2B-K1091T along with GluN1 in HEK 293T cells, we observed significant defects in its interactions with postsynaptic density 95. It is accompanied by reduced delivery of the receptors to the cell membrane and a decrease in glutamate affinity. Moreover, primary neurons expressing GluN2B-K1091T also exhibited impaired surface expression of NMDA receptors, a reduction in dendritic spine number and excitatory synaptic transmission. In summary, our study reports a novel GRIN2B mutation and provides functional characteristics of this mutation in vitro, thereby contributing to the understanding of GRIN2B variants in epilepsy and ID.
癫痫是一种神经疾病，在智力障碍（ID）个体中广泛存在。已证实 N-甲基-D-天冬氨酸（NMDA）受体在癫痫和 ID 中都发挥着重要作用。GRIN2B 基因的常染色体显性突变，该基因编码 NMDA 受体的 GluN2B 亚基，已被报道与癫痫和 ID 相关。然而，这种关联的潜在机制尚不清楚。在这项研究中，我们在一名癫痫伴 ID 的患者中发现了一种新的 GRIN2B 突变（c.3272A>C，p.K1091T）。先证者为一名 1 岁 10 个月大的女孩，GRIN2B 变异来自于其母亲。我们进一步研究了该突变的功能后果。我们的研究结果表明，p.K1091T 突变创造了一个酪蛋白激酶 2 磷酸化位点。使用包含 GluN2B-K1091T 和 GluN1 的重组 NMDA 受体在 HEK 293T 细胞中，我们观察到其与突触后密度蛋白 95 的相互作用显著缺陷。这伴随着受体向细胞膜的传递减少和谷氨酸亲和力降低。此外，表达 GluN2B-K1091T 的原代神经元也表现出 NMDA 受体表面表达受损，树突棘数量减少和兴奋性突触传递减少。总之，我们的研究报告了一种新的 GRIN2B 突变，并提供了该突变在体外的功能特征，从而有助于理解 GRIN2B 变异在癫痫和 ID 中的作用。
