A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes

The metabotropic glutamate receptor 7 (mGlu(7)) 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 mGlu(7) ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu(7)-I154T mutant reveal that this substitution resulted in significant loss of mGlu(7) protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu(7)–global KO mice, mGlu(7)-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu(7) receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.