GRIA1
The GRIA1 gene encodes the Glutamate Ionotropic Receptor AMPA Type Subunit 1 (GluA1), an essential mediator of excitatory synaptic transmission in the brain. Pathogenic variants in GRIA1 have been identified throughout the coding sequence and are associated with a broad spectrum of neurodevelopmental symptoms, including cognitive delay, speech and language impairments, seizures or epilepsy, behavioral challenges, and hypotonia; EEG abnormalities are also common. Most GRIA1-related disorders follow an autosomal dominant pattern and often arise de novo rather than being inherited. Functionally, these variants converge on AMPA receptor dysfunction, highlighting its central role in neurodevelopment.
Biological Function
GluA1 is one of four subunits (GluA1–4) that assemble to form AMPA receptors (AMPARs), and it represents the most abundant of these subunits. AMPARs are the principal mediators of fast excitatory neurotransmission in the central nervous system and also play essential roles in calcium signaling, synaptic plasticity, and the structural and developmental organization of synapses.
Mutations
Studies have identified mutations in human patients with neurodevelopmental and other brain disorders. Two representative examples are listed below.
A 2022 study by Ismail et al. 2022 (PMID: 35675825) reported missense & truncating variants in Neurodevelopmental Disorder (NDD). This study reported seven unrelated individuals carrying rare GRIA1 variants, including:
p.Ala636Thr (c.1906 G>A)
p.Ile627Thr (c.1880 T>C)
p.Gly745Asp (c.2234 G>A)
p.Arg345Gln (c.1034 G>A)
p.Arg377Ter (c.1129 C>T)
A 2017 study by Geisheker et al. (PMID: 28628100) identified seven GRIA1 mutations in patients with neurodevelopmental disorders (NDDs). All of these variants cluster near the M3 transmembrane region, which plays a critical role in channel gating. Among them, the p.Ala636Thr mutation was recurrent, observed in five independent individuals. The reported variants in this study include:
p.Ile627Thr (c.1880T>C)
p.Ala636Thr (c.1906G>A)
p.Val640Leu (c.1918G>C)
Research at Northwestern
Research projects at CAN are investigating how GRIA1 mutations contribute to neurodevelopmental disorders, with the long-term goal of translating these findings into new therapeutic strategies. In the Anis Contractor lab, ongoing efforts include generating mouse models carrying same mutations found in human patient and examining how these variants disrupt synaptic function and behavior. These new GRIA1 mouse models offer critical insight into the pathological mechanisms underlying GRIA1 mutations and hold strong potential for guiding the development of novel therapies—ultimately aiming to improve outcomes for affected individuals.
Clinical Trials
Currently, there are no active clinical trials specifically targeting diseases caused by mutations in the GRIA1 gene However, clinical trials are underway for disorders associated with mutations in GRIN genes, which encode NMDA-type ionotropic glutamate receptors (iGluRs) (https://clinicaltrials.gov/).
Patient advocacy organizations
GRIA1 is member of the ionotropic glutamate receptor (iGluR) family, which encompasses numerous genes encoding receptor subunits, including GRIA1–4, GRID1–2, GRIN (seven genes), and GRIK1–5. Mutations have been identified across many of these iGluR genes. Collectively, disorders resulting from such mutations are referred to as GRI disorders. The CureGRIN Foundation is a leading organization that provides support for individuals and families affected by GRI disorders, offering education, resources, and advocacy.