Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "Giannina Gaslini", 16147, Genoa, Italy.
Nat Commun. 2019 Jul 12;10(1):3094. doi: 10.1038/s41467-019-10910-w.
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations 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, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
AMPA 受体 (AMPARs) 是由 GluA1-4 亚基组成的四聚体配体门控通道，这些亚基由 GRIA1-4 基因编码。GluA2 具有特别重要的作用，因为在 Q607 位点的转录后编辑之后，它使异源多聚体 AMPAR 对 Ca2+ 不可渗透，电流与跨膜电压之间呈线性关系。在这里，我们报道了 28 名无亲缘关系的智力障碍 (ID) 患者和神经发育异常患者（包括自闭症谱系障碍 (ASD)、雷特综合征样特征以及癫痫或发育性癫痫性脑病 (DEE)）中存在杂合性新生 GRIA2 突变。在功能表达研究中，与野生型通道相比，突变导致由突变亚基介导的激动剂诱导电流减少。当 GluA2 亚基与 GluA1 共表达时，大多数 GRIA2 突变会导致电流幅度减小，有些还会影响电压整流。我们的研究结果表明，GRIA2 中的新生变异可导致神经发育障碍，补充了其他导致 ID、ASD 和 DEE 的遗传原因也会破坏谷氨酸能突触传递的证据。
