Abstract
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.
Highlights
The metabotropic glutamate receptors are a class of G protein–coupled receptors that bind glutamate, the major excitatory neurotransmitter, and activate intracellular signaling pathways that modulate synaptic transmission and plasticity [1]
Heterozygous deletions and point mutations have been reported in patients with autism spectrum disorder (ASD) [5,6,7] and attention deficit hyperactivity disorder [8], whereas homozygous point mutations have been found in rare cases of severe developmental delay, microcephaly, and epilepsy [9,10,11]
We have identified a family from Saudi Arabia in which the recessive GRM7 variant c.461T>C p.Ile154Thr segregates with severe developmental delay
Summary
The metabotropic glutamate (mGlu) receptors are a class of G protein–coupled receptors that bind glutamate, the major excitatory neurotransmitter, and activate intracellular signaling pathways that modulate synaptic transmission and plasticity [1]. Whole exome sequencing (WES) studies have identified rare deletions and variants in GRM7, the human gene encoding mGlu, in patients with neurodevelopmental disorders. We present new clinical cases of 2 sisters with severe developmental delay and epilepsy confirmed to be homozygous for a GRM7 variant c.461T>C p.Ile154Thr (mGlu7-I154T). This variant was first identified by WES in 2 brothers in 2016, and detailed clinical information was recently published [9, 11]. Functional studies of the mGlu7-I154T mutant protein in HEK293A cells and knockin mice reveal that this single amino acid change is sufficient to substantially reduce mGlu protein levels and produce a range of neurological phenotypes in mice, providing further support for GRM7 as a causative gene in neurodevelopmental disorders
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