Department of Pharmacology and.
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA.
JCI Insight. 2021 Feb 22;6(4):143324. doi: 10.1172/jci.insight.143324.
The metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution resulted in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu7-global KO mice, mGlu7-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.
代谢型谷氨酸受体 7（mGlu7）是一种 G 蛋白偶联受体，最近与神经发育障碍有关。这种关联得到了自闭症谱系障碍、注意力缺陷多动障碍和严重发育迟缓患者中 GRM7 变异体的鉴定的支持。先前在 2 名患者中报道的一种 GRM7 突变导致 mGlu7 配体结合域内的单个氨基酸变化，即 I154T。在这里，我们报告了 2 名具有这种突变的新患者，他们表现出严重的发育迟缓和癫痫。对 mGlu7-I154T 突变体的功能研究表明，这种取代导致 HEK293A 细胞和小鼠中 mGlu7 蛋白表达的显著丧失。我们表明，这是在蛋白质表达和运输的转录后水平发生的。与 mGlu7-全局 KO 小鼠类似，mGlu7-I154T 动物表现出运动协调能力降低、情景恐惧学习缺陷和癫痫发作。这提供了功能证据，表明影响 mGlu7 受体的疾病相关突变足以在小鼠中引起神经功能障碍，并进一步验证了 GRM7 是人类中的致病基因。
