AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
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AMPA 受体 GluA2 亚基缺陷是神经发育障碍的原因
DOI：
10.1038/s41467-019-10910-w
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发表时间：
2019-07-12
影响因子：
16.6
通讯作者：
Tucci, Arianna
中科院分区：
文献类型：
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作者：
Salpietro, Vincenzo;Dixon, Christine L.;Tucci, Arianna
AMPA受体(AMPAR)是由GRIA1-4基因编码的GluA1-4亚基组成的四聚体配体门控通道。GluA2具有特别重要的作用，因为在Q607位点进行转录后编辑后，它使异多聚体AMPAR不透钙，电流和跨膜电压呈线性关系。在这里，我们报告了28例与智力残疾(ID)和神经发育异常(包括自闭症谱系障碍(ASD)、Rett综合征样特征和癫痫发作或发育性癫痫脑病(DeE))无关的患者的GRIA2杂合性突变。在功能表达研究中，突变导致由突变亚基介导的激动剂诱发电流比野生型通道减少。当GluA2亚基与GluA1共表达时，大多数GRIA2突变会导致电流幅度降低，有些还会影响电压整流。我们的结果表明，GRIA2中的去新变量可以导致神经发育障碍，补充了ID、ASD和DIE的其他遗传原因也扰乱谷氨酸能突触传递的证据。
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded byGRIA1-4genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygousde novo GRIA2mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, mostGRIA2mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show thatde-novovariants inGRIA2can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.