A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes
Nicole M Fisher1,2, Aqeela AlHashim3, Aditi B Buch1,2
1Department of Pharmacology and.
JCI Insight
|January 21, 2021
Summary
A mutation in the metabotropic glutamate receptor 7 (mGlu7) gene causes severe developmental delay and epilepsy by disrupting protein expression. This research validates GRM7 as a disease-causing gene for neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Metabotropic glutamate receptor 7 (mGlu7) is implicated in neurodevelopmental disorders.
- GRM7 variants are found in patients with autism, ADHD, and developmental delay.
- A specific GRM7 mutation (I154T) affects the mGlu7 ligand-binding domain.
Purpose of the Study:
- To investigate the functional impact of the mGlu7-I154T mutation.
- To determine if this mutation causes neurological dysfunction.
- To further validate GRM7 as a disease-causing gene.
Main Methods:
- Studied mGlu7-I154T mutant in HEK293A cells and mice.
- Analyzed protein expression and trafficking.
- Assessed motor coordination, learning, and seizure activity in mGlu7-I154T mice.
Main Results:
- The mGlu7-I154T mutation significantly reduced mGlu7 protein expression post-transcriptionally.
- mGlu7-I154T mice showed impaired motor coordination and contextual fear learning.
- mGlu7-I154T mice exhibited seizures, similar to mGlu7-global KO mice.
Conclusions:
- The I154T mutation in GRM7 leads to loss of mGlu7 protein expression and trafficking.
- This mutation is sufficient to cause neurological dysfunction, including seizures.
- GRM7 is validated as a disease-causing gene for neurodevelopmental disorders.
