A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes.

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 two patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report two new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution results in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurs post-transcriptionally at the level of protein expression and trafficking. Similar to mGlu7 global knockout mice, mGlu7-I154T animals exhibit reduced motor coordination, deficits in contextual fear learning, and seizures. This provides the first functional evidence that a disease-associated mutation affecting the mGlu7 receptor is sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.