Alternative titles; symbols
HGNC Approved Gene Symbol: GRIA1
Cytogenetic location: 5q33.2 Genomic coordinates (GRCh38): 5:153,489,615-153,813,869 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q33.2 | ?Intellectual developmental disorder, autosomal recessive 76 | 619931 | Autosomal recessive | 3 |
| Intellectual developmental disorder, autosomal dominant 67 | 619927 | Autosomal dominant | 3 |
The GRIA1 gene encodes a subunit of ionotropic glutamate AMPA receptors, which are ligand-gated cation channels that mediate the majority of excitatory synaptic transmission in the central nervous system and play a role in synaptic plasticity mechanisms thought to underlie learning and memory (summary by Ismail et al., 2022).
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. Thus, glutamate receptors have been named according to their respective agonists, the N-methyl-D-aspartate (NMDA; 138249), quisqualic acid (QUIS), kainate (KA), and 2-amino-4-phosphonobutyrate (AP4) receptors.
Puckett et al. (1991) isolated and sequenced a human glutamate receptor cDNA. The sequence of GLUR1 was predicted to encode a 907-amino acid protein that had 97% identity to one of the rodent kainate receptor subunits. GLUR1 mRNA is widely expressed in human brain.
The C-terminal halves of the GLUR channels contain 4 transmembrane regions. Sommer et al. (1990) determined that a small segment preceding the fourth transmembrane region in each GLUR channel subunit exists in 2 versions that have different amino acid sequences. These modules, designated 'flip' and 'flop,' are encoded by adjacent exons. About half of the GLUR cDNAs isolated from rat brain libraries specified the flip sequence, and the other half specified the flop sequence. Within rat brain, the flip versions of GLURA, GLURB (GRIA2; 138247), and GLURC (GRIA3; 305915) were detected in CA3 neurons of the hippocampus, while both versions of these receptors and GLURD (GRIA4; 138246) were found in CA1 neurons. Other central nervous system regions showed differential expression of flip and flop modules for each of the GLUR genes.
Using in situ hybridization, McLaughlin et al. (1993) found that expression of GLURA and GLURB in human hippocampus differed from their expression in rat hippocampus. In human, both genes were preferentially expressed in the dentate gyrus and CA1 regions, with lower expression in CA3. An exception was GLURB flop, which showed lower expression in CA3 than in dentate gyrus.
Crystal Structure
Nakagawa et al. (2005) presented the structure of native AMPA receptors purified from rat brain as determined by single-particle electron microscopy. Unlike the homotetrameric recombinant GluR2, the native heterotetrameric AMPA receptor adopted various conformations, which reflected primarily a variable separation of the 2 dimeric extracellular N-terminal domains. Members of the stargazin/TARP (602911) family of transmembrane proteins copurified with AMPA receptors and contributed to the density representing the transmembrane region of the complex. Glutamate and cyclothiazide markedly altered the conformational equilibrium of the channel complex, suggesting that desensitization is related to separation of the N-terminal domains.
Cryoelectron Microscopy
Herguedas et al. (2019) presented a cryoelectron microscopy structure of the heteromeric GluA1/GluA2 (138247) receptor associated with 2 transmembrane AMPAR regulatory protein (TARP) gamma-8 (606900) auxiliary subunits, the principal AMPAR complex at hippocampal synapses. Within the receptor, the core subunits arrange to give the GluA2 subunit dominant control of gating. This structure revealed the geometry of the Q/R site that controls calcium flux, suggested association of TARP-stabilized lipids, and demonstrated that the extracellular loop of gamma-8 modulates gating by selectively interacting with the GluA2 ligand-binding domain.
Zhao et al. (2019) elucidated the structures of 10 distinct native AMPA receptor complexes by single-particle cryoelectron microscopy and found that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. GluA1 predominantly accesses the A or C positions. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.
Puckett et al. (1991) mapped the GLUR1 gene to 5q33 by in situ hybridization. Although no human neurogenetic disorder in the region of 5q33 was known, 5 neurologic mutations were known to reside on the homologous region on mouse chromosome 11. Using Southern analysis on a somatic cell hybrid mapping panel, Sun et al. (1992) mapped the GLUR1 gene to chromosome 5. Use of a panel of 7 additional somatic cell hybrids permitted sublocalization to 5q31.3-q33.3. In the course of construction of a radiation hybrid map of 18 genes on distal 5q, Warrington et al. (1992) determined that the GLR1 gene, as they called it, is situated, with a high probability, between CSF1R (164770) proximally and NKSF2 (161561) distally. Using PCR with a panel of DNA from an interspecific backcross, and through RFLV and haplotype analyses, Gregor et al. (1993) mapped the Glur1 gene in the mouse to a region of chromosome 11 in which loci for neurologic mutations, i.e., 'vibrator,' 'shaker-2,' 'tipsy,' and 'spasmodic,' have been mapped.
Stumpf (2022) mapped the GRIA1 gene to chromosome 5q33.2 based on an alignment of the GRIA1 sequence (GenBank AK315934) with the genomic sequence (GRCh38).
Sommer et al. (1990) determined that the flip and flop versions of the rat GLUR genes impart different pharmacologic and kinetic properties on currents evoked by L-glutamate or AMPA, but they do not differ in their response to kainate. The authors concluded that the exon switching may underlie adaptive changes in neurons such as synaptic plasticity.
To monitor changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, Shi et al. (1999) tagged the AMPA receptor subunit GluR1 with green fluorescent protein (GFP). GluR1-GFP was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with 2-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines, as well as clusters in dendrite shafts. As they could be blocked by NMDA receptor antagonists, these postsynaptic trafficking events required synaptic NMDA receptor activation, and Shi et al. (1999) concluded that they may contribute to the enhanced AMPA receptor-mediated transmission observed during long-term potentiation and activity-dependent synaptic maturation.
Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA receptor phosphorylation. Lee et al. (2000) showed that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GLUR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, Lee et al. (2000) found that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GLUR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cAMP-dependent protein kinase (PKA; see 176911) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII; see 602123) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors, depending on the history of the synapse. Lee et al. (2000) concluded that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.
Mack et al. (2001) demonstrated that plasticity of mature hippocampal CA1 synapses could be restored by controlled expression of GFP-tagged GluR-A in GluR-A-deficient mice. GFP-tagged GluR-A contributed to channel formation and displayed the developmental redistribution of AMPA receptors in CA1 pyramidal neurons. Long-term potentiation induced by pairing or tetanic stimulation was rescued in adult GluR-A-null mice when GFP-GluR-A expression was constitutive or induced in already fully developed pyramidal cells. Mack et al. (2001) concluded that GluR-A-independent forms of synaptic plasticity can mediate the establishment of mature hippocampal circuits that are prebuilt to express GluR-A-dependent long-term potentiation.
By yeast 2-hybrid analysis of mouse forebrain, Uemura et al. (2002) identified a possible interaction between Gria1 and the Golgi-specific zinc finger protein Godz (ZDHHC3; 617150). Immunoprecipitation analysis suggested that Godz and Gria1 did not interact directly, but coexpression of Godz affected the subcellular localization of Gria1, causing increased Gria1 localization at the Golgi apparatus.
Sutton et al. (2003) demonstrated that extinction training during the withdrawal from chronic cocaine self-administration in rats induces experience-dependent increases in the GLUR1 and GLUR2 (138247)/GLUR3 (305915) subunits of AMPA glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GLUR1 subunit were positively associated with a level of extinction achieved during training, suggesting that GLUR1 may promote extinction of cocaine seeking. Sutton et al. (2003) showed that viral-mediated overexpression of both GLUR1 and GLUR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GLUR subunit overexpression, attenuated stress-induced relapse to cocaine seeking even after GLUR overexpression declined. Sutton et al. (2003) concluded that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.
Takahashi et al. (2003) examined the trafficking of AMPA glutamate receptors into synapses in the developing rat barrel cortex. In vivo gene delivery was combined with in vitro recordings to show that experience drives recombinant GluR1 into synapses formed between layer 4 and layer 2/3 neurons. Moreover, expression of the GluR1 cytoplasmic tail, a construct that inhibits synaptic delivery of endogenous AMPA glutamate receptors during long-term potentiation, blocked experience-driven synaptic potentiation. In general, synaptic incorporation of AMPA glutamate receptors in vivo conforms to rules identified in vitro and contributes to plasticity driven by natural stimuli in the mammalian brain.
Park et al. (2004) reported that AMPA receptors are transported from recycling endosomes to the plasma membrane for long-term potentiation. Stimuli that triggered long-term potentiation promoted not only AMPA receptor insertion but also generalized recycling of cargo and membrane from endocytic compartments. Thus, Park et al. (2004) concluded that recycling endosomes supply AMPA receptors for long-term potentiation and provide a mechanistic link between synaptic potentiation and membrane remodeling during synapse modification.
Rumpel et al. (2005) reported that fear conditioning drives AMPA-type glutamate receptors into the synapse of a large fraction of postsynaptic neurons in the lateral amygdala, a brain structure essential for this learning process. Furthermore, memory was reduced if AMPA receptor synaptic incorporation was blocked in as few as 10 to 20% of lateral amygdala neurons. Thus, Rumpel et al. (2005) concluded that the encoding of memories in the lateral amygdala is mediated by AMPA receptor trafficking, is widely distributed, and displays little redundancy.
Matsuo et al. (2008) studied the dynamics of newly synthesized AMPA-type glutamate receptors (AMPARs) induced with learning using transgenic mice expressing the GluR1 subunit fused to green fluorescent protein (GFP-GluR1) under control of the c-fos (164810) promoter. Matsuo et al. (2008) found learning-associated recruitment of newly synthesized GFP-GluR1 selectively to mushroom-type spines in adult hippocampal CA1 neurons 24 hours after fear conditioning. Their results were consistent with a synaptic tagging model which allows activated synapses to subsequently capture newly synthesized receptor, and also demonstrated a critical functional distinction in the mushroom spines with learning.
Schwenk et al. (2009) demonstrated by proteomic analysis that the majority of AMPA receptors in the rat brain are coassembled with 2 members of the cornichon family of transmembrane proteins, rather than with the transmembrane AMPA receptor regulatory proteins (TARPs). Coassembly with cornichon homologs 2 (CNIH2; 611288) and CNIH3 affects AMPA receptors in 2 ways: cornichons increase surface expression of AMPA receptors, and they alter channel gating by markedly slowing deactivation and desensitization kinetics. Schwenk et al. (2009) concluded that their results demonstrated that cornichons are intrinsic auxiliary subunits of native AMPA receptors and provide molecular determinants for glutamatergic neurotransmission in the central nervous system.
Clem and Huganir (2010) found that a central component of extinction-induced erasure is the synaptic removal of calcium-permeable AMPA receptors in the lateral amygdala. A transient upregulation of this form of plasticity, which involves phosphorylation of the GluR1 subunit of the AMPA receptor, defines a temporal window in which fear memory can be degraded by behavioral experience. Clem and Huganir (2010) concluded that their results revealed a molecular mechanism for fear erasure and the relative instability of recent memory.
Allen et al. (2012) used biochemical fractionation of astrocyte-conditioned medium to identify glypican-4 (GPC4; 300168) and glypican-6 (GPC6; 604404) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and showed that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of GPC4 to purified neurons was sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This was achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA glutamate receptor (AMPAR). GPC4 and GPC6 are expressed in astrocytes in vivo in the developing central nervous system (CNS), with GPC4 expression enriched in the hippocampus and GPC6 enriched in the cerebellum. Finally, Allen et al. (2012) demonstrated that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. Allen et al. (2012) concluded that their data identified glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.
In the cerebellum, Bergmann glial (BG) cells express AMPA-type glutamate receptors composed exclusively of GluA1 and/or GluA4 (138246) subunits. Using conditional gene inactivation, Saab et al. (2012) found that the majority of cerebellar GluA1/A4-type AMPARs are expressed in BG cells. In young mice, deletion of BG AMPARs resulted in retraction of glial appendages from Purkinje cell synapses, increased amplitude and duration of evoked Purkinje cell currents, and a delayed formation of glutamatergic synapses. In adult mice, AMPAR inactivation also caused retraction of glial processes. The physiologic and structural changes were accompanied by behavioral impairments in fine motor coordination. Thus, Saab et al. (2012) concluded that BG AMPARs are essential to optimize synaptic integration and cerebellar output function throughout life.
To find the minimum necessary requirement of the GluA1 C tail for long-term potentiation (LTP) in mouse CA1 hippocampal pyramidal neurons, Granger et al. (2013) used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors (GRIA1, GRIA2, 138247, and GRIA3, 305915) with transfected subunits. In contrast to the prevailing model, Granger et al. (2013) found no requirement for the GluA1 C tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. Granger et al. (2013) concluded that their results demonstrated the synapse's remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in thinking with regard to the core molecular events underlying synaptic plasticity. In an accompanying commentary, Sheng (2013) suggested that the data of Granger et al. (2013) showed that, at least in the context of neurons lacking AMPA receptors, several different kinds of glutamate receptor can be recruited to synapses and are sufficient to support LTP, irrespective of their C tails and presumably regardless of their associated proteins and accessory subunits. Malinow and Huganir (2013) suggested that the complete lack of AMPA receptors may fundamentally change AMPA receptor trafficking compared with that in normal synapses, and argued that the C tail endows GluA1 with a competitive advantage to reach the synapse. Both commentaries suggested that the findings of Granger et al. (2013) will prompt investigation of the structural changes that occur in the synapse during and after LTP.
Autosomal Dominant Intellectual Developmental Disorder 67
In a girl with autosomal dominant intellectual developmental disorder-67 (MRD67; 619927), de Ligt et al. (2012) identified a de novo heterozygous missense mutation in the GRIA1 gene (A636T; 138248.0001). Functional studies of the variant were not performed. The patient was ascertained from a cohort of 100 patients with severe intellectual disability who underwent exome sequencing.
Geisheker et al. (2017) identified a recurrent heterozygous A636T mutation in the GRIA1 gene in 3 unrelated patients with MRD67. The mutation was demonstrated to occur de novo in 1 patient; paternal DNA was not available for the other 2 patients, but the mutation was not present in either mother. The mutation, which occurred within a highly conserved region in the M3 transmembrane domain, was not present in the ExAC database. In vitro functional expression studies in HEK293 cells transfected with the mutant protein showed presence of a constitutive current, consistent with a gain-of-function effect, although a dominant effect of the mutation was not observed when cotransfected with wildtype GRIA1. The authors suggested that the mutation may cause a defect in early synaptic development. The study of Geisheker et al. (2017) included a large cohort of over 17,000 patients with a diagnosis of ASD or developmental delay who underwent genetic studies. Geisheker et al. (2017) noted that De Rubeis et al. (2014) had identified a de novo A636T mutation in a patient from a large cohort of patients with ASD who underwent exome sequencing. Clinical details were not provided.
Ismail et al. (2022) identified a de novo heterozygous A636T mutation in 2 unrelated patients (P3 and P4) with MRD67. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Xenopus oocytes expressing the A636T mutation showed a 10-fold increased current, impaired desensitization, increased sensitivity towards glu, and increased channel-opening ability compared to controls. These findings were consistent with a gain-of-function effect. In a 21-year-old woman (patient 6) with MRD67, Ismail et al. (2022) identified a different de novo heterozygous missense variant in the GRIA1 gene (G745D; 138248.0002). The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the G745D variant resulted in decreased current amplitudes compared to controls, suggesting a loss-of-function effect. However, there was also evidence for decreased desensitization and increased kainate/glu ratio of the mutant channel, which would suggest increased current. Ismail et al. (2022) also reported a patient (P5), originally reported by Geisheker et al. (2017) (patient 25431) with MRD67 associated associated with a de novo heterozygous I627T variant in the GRIA1 gene that was demonstrated to show a loss-of-function effect in in vitro studies. Of note, P5 also carried duplications of 18p11 and Xq26.1 and had a family history of learning difficulties.
Autosomal Recessive Intellectual Developmental Disorder 76
In a 10-year-old girl (patient 1), born of consanguineous parents, with autosomal recessive intellectual developmental disorder-76 (MRT76; 619931), Ismail et al. (2022) identified a homozygous nonsense mutation in the GRIA1 gene (R377X; 138248.0003). Each parent was heterozygous for the mutation, which was not present in the gnomAD database. Baralle (2024) stated that the mutation was found by whole-exome sequencing (WES) and that the parents were unaffected. In vitro functional expression studies showed that the mutation truncates the protein, prevented proper subunit assembly and function, and did not produce any current response to glu stimulation, resulting in a complete loss of function.
Zamanillo et al. (1999) generated mice lacking the AMPA receptor subunit GluRA, also known as GluR1, by homologous recombination. Homozygous knockout mice exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. They were smaller than their littermates during the first postnatal weeks, but after weaning their size was normal. In hippocampal CA1 pyramidal neurons, GluRA -/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced but glutamatergic synaptic currents were unaltered; evoked dendritic and spinous calcium currents, calcium-dependent gene activation, and hippocampal field potentials were as in wildtype. In adult GluRA -/- mice, associative long-term potentiation was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggested to Zamanillo et al. (1999) that CA1 hippocampal long-term potentiation is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between long-term potentiation in CA1 and acquisition of spatial memory.
Phosphorylation of the GLUR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GLUR1 phosphorylation is necessary for plasticity and learning and memory, Lee et al. (2003) generated mice with knockin mutations in the Glur1 phosphorylation sites. The phosphomutant mice showed deficits in LTD and LTP and had memory defects in spatial learning tasks. These results demonstrated that phosphorylation of GLUR1 is critical for LTD and LTP expression and the retention of memories.
Ismail et al. (2022) found that homozygous knockdown of the gria1 gene in Xenopus tadpoles resulted in early transient motor deficits and some behavioral abnormalities that could be consistent with seizures. Although mutant animals had no obvious or consistent craniofacial or structural brain abnormalities, they showed impaired spatial memory in an alternative choice search pattern assay. These findings suggested that disruption of glutamatergic signaling impairs normal behavior and possibly affects cognition in vertebrates.
In a girl (patient 2) with autosomal dominant intellectual developmental disorder-67 (MRD67; 619927), de Ligt et al. (2012) identified a heterozygous de novo c.1906G-A transition (c.1906G-A, NM_001114183.1) in the GRIA1 gene, resulting in an ala636-to-thr (A636T) substitution. Born after an uncomplicated pregnancy and delivery, she showed global developmental delay with impaired intellectual development and no speech. Brain imaging was normal; she did not have seizures. Functional studies of the variant were not performed.
Geisheker et al. (2017) identified a recurrent heterozygous A636T mutation in the GRIA1 gene in 3 unrelated patients with MRD67. The mutation was demonstrated to occur de novo in 1 patient; paternal DNA was not available for the other 2 patients, but the mutation was not present in either mother. The mutation, which occurred within a highly conserved region in the M3 transmembrane domain, was not present in the ExAC database. In vitro functional expression studies in HEK293 cells transfected with the mutation showed presence of a constitutive current, consistent with a gain-of-function effect, although a dominant effect of the mutation was not observed when cotransfected with wildtype GRIA1. The authors suggested that the mutation may cause a defect in early synaptic development. Phenotypic information from 4 patients with the mutation (including the patient reported by de Ligt et al., 2012) showed that all had autism spectrum disorder (ASD) and mild to moderate intellectual disability with variable speech delay and other behavioral abnormalities, including ADHD, OCD, and motor tics. One patient had seizures between ages 2 and 5. The study of Geisheker et al. (2017) included a large cohort of over 17,000 patients with a diagnosis of ASD or developmental delay who underwent genetic studies. Geisheker et al. (2017) noted that De Rubeis et al. (2014) had identified a de novo A636T mutation in a patient from a large cohort of patients with ASD who underwent exome sequencing. Clinical details were not provided.
Ismail et al. (2022) identified a de novo heterozygous A636T mutation in 2 unrelated patients (P3 and P4) with MRD67. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Xenopus oocytes expressing the A636T mutation showed a 10-fold increased current, impaired desensitization, increased sensitivity towards glu, and increased channel-opening ability compared to controls. These findings were consistent with a gain-of-function effect.
In a 21-year-old woman (patient 6) with autosomal dominant intellectual developmental disorder-67 (MRD67; 619927), Ismail et al. (2022) identified a de novo heterozygous c.2234G-A transition (c.2234G-A, NM_000827.3) in the GRIA1 gene, resulting in a gly745-to-asp (G745D) substitution in ABD domain that contains the glutamate binding site. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the G745D variant resulted in decreased current amplitudes compared to controls, suggesting a loss-of-function effect. However, there was also evidence for decreased desensitization and increased kainate/glu ratio of the mutant channel, which would suggest increased current.
In a 10-year-old girl (patient 1), born of consanguineous parents, with autosomal recessive intellectual developmental disorder-76 (MRT76; 619931), Ismail et al. (2022) identified a homozygous c.1129C-T transition (c.1129C-T, NM_000827.3) in the GRIA1 gene, resulting in an arg377-to-ter (R377X) substitution. Each parent was heterozygous for the mutation, which was not present in the gnomAD database. Baralle (2024) stated that the mutation was found by whole-exome sequencing (WES) and that the parents were unaffected. In vitro functional expression studies showed that the mutation truncates the protein, prevented proper subunit assembly and function, and did not produce any current response to glu stimulation, resulting in a complete loss of function. Expression of a homozygous loss-of-function mutation similar to R377X in Xenopus tadpoles using CRISPR/Cas9 techniques resulted in early transient motor deficits and some behavioral abnormalities that could be consistent with seizures. Although mutant animals had no obvious or consistent craniofacial or structural brain abnormalities, they showed impaired spatial memory in an alternative choice search pattern assay. These findings suggested that disruption of glutamatergic signaling impairs normal behavior and possibly affects cognition.
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