智力障碍是一种常见的开始于儿童时期的神经系统发育疾病，主要表现为智力低下和适应功能受损。重度智力障碍主要由遗传学因素导致，因此对染色体异常或基因突变导致智力障碍的机制进行深入研究，有利于为针对性预防和治疗提供指导。NMDA受体GluN2A亚基参与突触可塑性调控，是目前已经确定的与智力障碍直接相关的蛋白之一。申请人在部分患有重度智力障碍的病人基因组中发现了新型GluN2A突变K879R。该突变位点位于受体羧基末端结构域（CTD）中一个高度保守的赖氨酸三联体（879-881KKK）中，可能与NMDA受体内质网滞留相关。为了理解该突变的致病机理，申请人拟制作GluN2A K879R基因敲入小鼠，综合利用分子生物学、生物化学和神经电生理技术，结合小鼠行为学分析手段，深入研究此新型突变导致智力障碍的分子机制。

Intellectual disability (ID) is a common childhood-onset neurodevelopmental disease. It is characterized by significantly impaired intellectual and adaptive functioning. Severe ID is mainly caused by genetic defects. Studying the mechanisms, by which various chromosomal anomalism or gene mutations cause ID, would be contributed to exploit definitive therapies. GluN2A subunit of NMDA receptor, which participates in synaptic plasticity, is a confirmed ID-relative protein. We discovered a novel GluN2A K879R mutation in a portion of ID patients. This mutation locates at a highly conserved lysine triplet (879-881KKK) of GluN2A carboxyl terminal domain (CTD), which might relate to endoplasmic reticulum retention of NMDA receptor. In order to understand the pathogenesis of GluN2A K879R mutation, we plan to make GluN2A K879R knock-in mouse. We would like to use molecular biological, biochemical and electrophysiological technologies, combining with behavior analysis, to study the molecular mechanism, by which the mutation-relative intellectual disability is induced.