A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes.
PMID 33476302 | PMCID PMC7934925 | DOI 10.1172/jci.insight.143324 · JCI insight · 2021
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.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | GRM7 | “A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes.” | 0.98 | hgnc_dict_v1 |
| phenotype | developmental delay | “A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | autism spectrum disorder | “This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | epilepsy | “Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | neurodevelopmental disorder | “The metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that has been recently linked to neurodevelopmental disorders.” | 0.93 | phenotype_alias_lexicon_v2 |
| population | Population | “One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain.” | 0.80 | saudi_context_rules_v1 |
| variant | I154T | “One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain.” | 0.82 | literature_variant_regex_v2 |