Glutamate is the most important excitatory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated ionotropic cation channel that is composed of several subunits and modulated by a glycine binding site. Many forms of synaptic plasticity depend on the influx of calcium ions through NMDA receptors, and NMDA receptor dysfunction has been linked to a number of neuropsychiatric disorders, including schizophrenia. Whole-exome sequencing was performed in a family with a strong history of psychotic disorders over three generations. We used an iterative strategy to obtain condense and meaningful variants. In this highly affected family, we found a frameshift mutation (rs10666583) in the GRIN3B gene, which codes for the GluN3B subunit of the NMDA receptor in all family members with a psychotic disorder, but not in the healthy relatives. Matsuno et al., also reported this null variant as a risk factor for schizophrenia in 2015. In a broader sample of 22 patients with psychosis, the allele frequency of the rs10666583 mutation variant was increased compared to those of healthy population samples and unaffected relatives. Compared to the 1000 Genomes Project population, we found a significant increase of this variant with a large effect size among patients. The amino acid shift degrades the S1/S2 glycine binding domain of the dominant modulatory GluN3B subunit of the NMDA receptor, which subsequently affects the permeability of the channel pore to calcium ions. A decreased glycine affinity for the GluN3B subunit might cause impaired functional capability of the NMDA receptor and could be an important risk factor for the pathogenesis of psychotic disorders.

中文翻译：

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GRIN3B错义突变是精神分裂症的遗传危险因素：在具有精神病史的家庭中进行全外显子测序。

谷氨酸是脑中最重要的兴奋性神经递质。N-甲基-D-天冬氨酸（NMDA）受体是谷氨酸门控离子阳离子通道，由几个亚基组成，并由甘氨酸结合位点调节。多种形式的突触可塑性取决于钙离子通过NMDA受体的流入，并且NMDA受体功能障碍已与许多神经精神疾病（包括精神分裂症）相关。全基因组测序是在一个有三代以上精神病病史的家庭中进行的。我们使用了一种迭代策略来获得压缩和有意义的变体。在这个受到高度影响的家庭中，我们在GRIN3B基因中发现了移码突变（rs10666583），该基因编码患有精神病的所有家庭成员NMDA受体的GluN3B亚基，但在健康的亲戚中却没有。Matsuno等人在2015年还报告了该无效变异体作为精神分裂症的危险因素。在更广泛的22位精神病患者样本中，与健康人群样本和未患病亲属相比，rs10666583变异变异体的等位基因频率增加。与1000个基因组计划的人群相比，我们发现这种变异显着增加，并且在患者中产生了很大的影响。氨基酸移位会降解NMDA受体的主要调节性GluN3B亚基的S1 / S2甘氨酸结合结构域，从而影响通道孔对钙离子的渗透性。