GRIA genes. This is the first time we are describing GRIA genes on this blog. GRIA genes, which include GRIA1, GRIA2, GRIA3, and GRIA4, encode the AMPA receptor, one of the two key channels in the process of glutamate neurotransmission. While GRIN genes, which encode the NMDA receptor, have been characterized much more extensively in the literature, GRIAs remain relatively under-characterized, even though their protein products are involved in a similar molecular process in the post-synapse in modulating excitatory synaptic transmission. Here, we provide a brief overview of the genetic and phenotypic range of GRIA-related disorders.
Mechanism. Glutamate neurotransmission through ionotropic receptors is governed by a somewhat complex molecular mechanism, which helps us better understand why individuals with disease-causing variants in GRIA present with complex neurodevelopmental disorders. After glutamate is released into the synaptic cleft, it arrives at the post-synaptic neuron and binds to NMDA and AMPA receptors, which are expressed close to each other. Binding of glutamate to the AMPA receptor then allows for sodium to enter the post-synaptic neuron, which causes local depolarization. This, in turn, forces out the Mg2+ ion that blocks the nearby NMDA receptor at rest. What is the rationale behind this series of events?
LTP. The coincidence of presynaptic glutamate release and removal of the magnesium block enables Na+ and Ca2+ ions to flow into the cell through the NMDA receptor, increase the depolarization, and help propagate the signal further. This constitutes the molecular basis of learning and memory: AMPA and NMDA receptors are involved in Long-Term Potentiation (LTP). In LTP, calcium flowing into the cell through the NMDA receptor causes a cascade of reactions that will result in more AMPA receptors being inserted into the membrane. This enhances synaptic plasticity – accordingly, the post-synaptic neuron becomes more sensitive to glutamate since there are more receptors present. In GRIA-related disorders, LTP and synaptic plasticity mechanisms are impaired.
Phenotypic and genetic landscape. As an under-characterized and relatively novel monogenic cause of neurodevelopmental disorders, GRIA genes do not have any specific genotype-phenotype associations. However, some studies pointed out interesting clinical features of individuals with GRIA-related disorders.
GRIA1. A cohort study of 9 individuals with GRIA1-related disorders reported an association between disease-causing mutations in GRIA1 and differences in cognition and speech, in addition to other features commonly noted in neurodevelopmental disorders, such as EEG abnormalities with or without seizures, language delay, and poor sleep. While authors of this study report one recurrent variant, p.Ala636Thr, in three individuals, this variant was not found to be associated with any particular phenotype. Interestingly, the functional study of this variant showed that it causes gain-of-function effects through increased glutamate sensitivity and loss of desensitization.
GRIA2. While genotype-phenotype associations are currently not clear for GRIA2-related disorders either, Salpietro and collaborators made several interesting observations about specific variants and clinical presentations. For example, three individuals carrying a recurrent p.Val647Leu variant had DEE and shared EEG features. The most severe outcome, however, was reported for two individuals with the p.Ala639Ser variant who experienced sudden unexplained death in epilepsy (SUDEP). Overall, individuals with GRIA2-related disorders presented with intellectual disability, autism, Rett syndrome-like symptoms, and seizures in some cases. As in many genetic epilepsies, the underlying basis for a more severe phenotype is not clear, however, in the two cases of SUDEP reported in this study, the highly conserved SYTANLAAF transmembrane region was affected. At the same time, not all individuals with mutations at this locus experienced SUDEP, so further studies are needed to determine the reason behind severity of presentations.
GRIA3. Unlike other GRIA genes, GRIA3 is an X-linked gene. Moreover, seizures were reported more frequently than for GRIA1 or GRIA2: 6 out of 19 individuals had epilepsy in the largest study on GRIA3-related disorders to date; epileptic encephalopathy was observed in some individuals too. Further studies focused on large-scale standardized assessment of individuals carrying GRIA3 variants is needed to better understand clinical features within this particular group of conditions.
GRIA4. As with GRIA3-related disorders, there have been relatively few studies on GRIA4-related disorders. In a study of five individuals with GRIA4-related disorders, four individuals had a variant in the highly conserved SYTANLAAF region, previously recognized in GRIA2-related disorders. Moreover, one of these four individuals had a p.Ala644Val variant, which was at the same location and motif as the previously reported recurrent p.Ala636Thr variant in GRIA1. No specific genotype-phenotype associations were found, but authors noted developmental delay, speech delay, seizures, and EEG abnormalities in individuals carrying GRIA4 variants.
What you need to know. GRIA-related disorders are a relatively new gene family that are causative of neurodevelopmental disorders. While AMPA channels – “the workhorse of glutamatergic transmission” – are critical in the process of excitatory neurotransmission and synaptic plasticity, GRIA genes remain relatively under-characterized, especially in comparison to GRIN genes. More studies are needed to better understand this group of disorders and delineate genotype-phenotype associations in individuals with disease-causing variants in GRIA genes.