McGill University and Douglas Hospital Research Institute, Department of Psychiatry, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3, Canada.
Montreal Neurological Institute, Department of Neurology and Neurosurgery, Montreal, QC H3A 2B4, Canada.
Stem Cell Reports. 2018 Jul 10;11(1):183-196. doi: 10.1016/j.stemcr.2018.05.018. Epub 2018 Jun 21.
Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses. Using electrophysiology and calcium imaging, we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors. It may be this function, in part, which underlies the neurological disease observed in patients with GRIN2B mutations.
GRIN2B 是 NMDA 受体的亚基，其杂合功能丧失突变可导致智力残疾和语言障碍。我们在人类细胞中 NMDA 受体谷氨酸结合域的编码区构建了 GRIN2B 缺失和功能丧失突变的克隆模型，并从携带同一结构域错义突变的患者中生成神经元。转录组分析显示，与细胞增殖相关的基因广泛增加，与神经元分化相关的基因减少，这一结果得到了广泛的蛋白质分析的支持。通过电生理学和钙成像，我们证明 NMDA 受体存在于神经祖细胞上，GRIN2B 中的人类突变甚至可以损害钙内流和膜去极化，即使在假定的未分化细胞状态下，这突出了非突触 NMDA 受体的重要作用。可能正是这种功能，部分导致了 GRIN2B 突变患者的神经病变。
