Alternative titles; symbols
HGNC Approved Gene Symbol: GRIA4
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38): 11:105,609,616-105,982,090 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.3 | Neurodevelopmental disorder with or without seizures and gait abnormalities | 617864 | Autosomal dominant | 3 |
The GRIA4 gene encodes a member of a family of L-glutamate-gated ion channels that mediate fast synaptic excitatory neurotransmission. These channels are also responsive to the glutamate agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) (Sommer et al., 1990).
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. In rat brain, the flip version of GLURD mRNA was only observed in cerebellum, whereas the flop version was only observed in forebrain. Other central nervous system regions showed differential expression of flip and flop modules for each of the GLUR genes.
Kawahara et al. (2004) identified a splice variant of human GLUR4, which they designated GLUR4c. This variant, which is distinct from the flip and flop GLUR4 variants, encodes a deduced 113-amino acid protein with a short C-terminal sequence following the fourth transmembrane domain. Real-time quantitative RT-PCR of adult and fetal specific brain regions found the GLUR4c variant most abundantly expressed in adult cerebellum and cortex. The level of GLUR4c expression was developmentally upregulated in cerebellum and cortex but remained low throughout development in other brain regions.
Martin et al. (2017) noted that Gria4 is found in the rat brain at high levels in CA1 pyramidal cells and the dentate gyrus of the hippocampus, in layers III and IV of the cerebral cortex, and in granule cells of the cerebellum.
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.
Because GLUR2 (GRIA2; 138247) is phosphorylated and its phosphorylation may mediate synaptic delivery, Correia et al. (2003) studied the biochemical interaction of GLUR4 with PKC-gamma (176980). They found that PKC-gamma interacted with the GLUR4 subunit in both rat brain and chick retina cultured neurons, and GLUR4-bound PKC-gamma preferentially phosphorylated GLUR4 on ser482 relative to other substrates. Cotransfection of PKC-gamma with GLUR4 in human embryonic kidney cells increased GLUR4 surface expression. Correia et al. (2003) concluded that PKC-gamma regulates the function of GLUR4-containing AMPA receptors.
Ouardouz et al. (2009) demonstrated that myelinated axons from rat spinal cord express functional GluR4-containing AMPA receptors capable of mediating a deleterious increase in intraaxonal calcium, resulting in axonal degeneration and white matter injury. The GluR4-mediated calcium increase was dependent on calcium-induced calcium release and ryanodine receptors (see, e.g., RYR1; 180901), and was unaffected by nitric oxide scavengers. Immunohistochemical studies showed GluR5 (GRIK1; 138245) and GluR4 clustered at the surface of myelinated axons.
In the cerebellum, Bergmann glial (BG) cells express AMPA-type glutamate receptors composed exclusively of GluA1 (138248) and/or GluA4 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.
Using PCR with DNA isolated from mapping panels of Chinese hamster/human hybrid cell lines and high-resolution fluorescence in situ suppression hybridization, McNamara et al. (1992) mapped the GLUR4 gene to 11q22-q23.
Using PCR with a panel of DNA from an interspecific backcross, and through RFLV and haplotype analyses, Gregor et al. (1993) mapped the Glur4 gene in the mouse to chromosome 9.
In 5 unrelated patients with neurodevelopmental disorder with or without seizures and gait abnormalities (NEDSGA; 617864), Martin et al. (2017) identified 5 different de novo heterozygous missense mutations in the GRIA4 gene (138246.0001-138246.0005). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Four of the mutations occurred in the highly conserved SYTANLAAF motif, which plays an important role in channel activation and gating. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling suggested that the location of 3 of the variants in the SYTANLAAF motif oriented toward the center of the pore region most likely would lead to disturbance of the gating mechanism allowing leakage or an open state, whereas the fourth variant in that motif likely results in reduced channel permeability. The fifth variant (R697P; 138246.0005), in the extracellular domain, was predicted to interfere with the binding between monomers. The least affected child (patient 5) carried the R697P variant, suggesting some degree of genotype/phenotype correlation. The mutations were predicted to have a dominant functional effect rather than to cause a loss of function.
Beyer et al. (2008) determined that the mouse spkw1 phenotype, which is prone to absence seizures, is caused by an insertion mutation in the Gria4 gene, resulting in decreased protein expression. Independently generated Gria4-null mice also developed frequent spike-wave discharges and did not complement spkw1 mice. Electrophysiologic studies showed that mutant Gria4 resulted in enhanced excitatory activity in the thalamic reticular nucleus by increasing the duration of synaptic responses. This could result in enhanced feed-forward inhibition from reticular neurons to thalamic relay neurons, with cortical effects. These results suggested an essential role for Gria4 in the brain, and indicated that abnormal AMPA receptor-dependent synaptic activity can be involved in absence seizures.
In a 15-year-old boy with neurodevelopmental disorder with seizures and gait abnormalities (NEDSGA; 617864), Martin et al. (2017) identified a de novo heterozygous c.1915A-T transversion (c.1915A-T, NM_000829.3) in the GRIA4 gene, resulting in a thr639-to-ser (T639S) substitution within the highly conserved SYTANLAAF motif near transmembrane 3. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would alter gating properties of the channel with inhibition of channel closing allowing leakage or an open state, resulting in constitutive channel opening. The authors postulated a dominant functional effect rather than a loss of function.
In a 21-year-old man with neurodevelopmental disorder with seizures and gait abnormalities (NEDSGA; 617864), Martin et al. (2017) identified a Martin et al. (2017) identified a de novo heterozygous c.1921A-G transition (c.1921A-G, NM_000829.3) in the GRIA4 gene, resulting in an asn641-to-asp (N641D) substitution within the highly conserved SYTANLAAF motif near transmembrane 3. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would inhibit the transition between the open and closed states or allow the channel to become trapped in an inactivated state, thus resulting in reduced channel permeability.
In a 4-year-old boy with neurodevelopmental disorder with seizures and gait abnormalities (NEDSGA; 617864), Martin et al. (2017) identified a de novo heterozygous c.1928C-G transversion (c.1928C-G, NM_000829.3) in the GRIA4 gene, resulting in an ala643-to-gly (A643G) substitution within the highly conserved SYTANLAAF motif near transmembrane 3. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would alter gating properties of the channel with inhibition of channel closing allowing leakage or an open state, resulting in constitutive channel opening. The authors postulated a dominant functional effect rather than a loss of function.
In a 4-year-old boy with neurodevelopmental disorder with seizures and gait abnormalities (NEDSGA; 617864), Martin et al. (2017) identified a de novo heterozygous c.1931C-T transition (c.1931C-T, NM_000829.3) in the GRIA4 gene, resulting in an ala644-to-val (A644V) substitution within the highly conserved SYTANLAAF motif near transmembrane 3. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would alter gating properties of the channel with inhibition of channel closing allowing leakage or an open state, resulting in constitutive channel opening. The authors postulated a dominant functional effect rather than a loss of function.
In a 4-year-old girl with neurodevelopmental disorder without seizures or gait abnormalities (NEDSGA; 617864), Martin et al. (2017) identified a de novo heterozygous c.2090G-C transversion (c.2090G-C, NM_000829.3) in the GRIA4 gene, resulting in an arg697-to-pro (R697P) substitution in the extracellular domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation may interfere with binding between monomers in a dominant manner. This patient had a milder phenotype compared to the other patients reported by Martin et al. (2017), suggesting some degree of genotype/phenotype correlation.
Beyer, B., Deleuze, C., Letts, V. A., Mahaffey, C. L., Boumil, R. M., Lew, T. A., Huguenard, J. R., Frankel, W. N. Absence seizures in C3H/HeJ and knockout mice caused by mutation of the AMPA receptor subunit Gria4. Hum. Molec. Genet. 17: 1738-1749, 2008. [PubMed: 18316356] [Full Text: https://doi.org/10.1093/hmg/ddn064]
Correia, S. S., Duarte, C. B., Faro, C. J., Pires, E. V., Carvalho, A. L. Protein kinase C-gamma associates directly with the GluR4 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit: effect on receptor phosphorylation. J. Biol. Chem. 278: 6307-6313, 2003. [PubMed: 12471040] [Full Text: https://doi.org/10.1074/jbc.M205587200]
Gregor, P., Reeves, R. H., Jabs, E. W., Yang, X., Dackowski, W., Rochelle, J. M., Brown, R. H., Jr., Haines, J. L., O'Hara, B. F., Uhl, G. R., Seldin, M. F. Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans. Proc. Nat. Acad. Sci. 90: 3053-3057, 1993. [PubMed: 8464923] [Full Text: https://doi.org/10.1073/pnas.90.7.3053]
Kawahara, Y., Ito, K., Sun, H., Ito, M., Kanazawa, I., Kwak, S. GluR4c, an alternative splicing isoform of GluR4, is abundantly expressed in adult human brain. Molec. Brain Res. 127: 150-155, 2004. [PubMed: 15306133] [Full Text: https://doi.org/10.1016/j.molbrainres.2004.05.020]
Martin, S., Chamberlin, A., Shinde, D. N., Hempel, M., Strom,T. M., Schreiber, A., Johannsen, J., Ousager, L. B., Larsen, M. J.,Hansen, L. K., Fatemi, A., Cohen, J. S., Lemke, J., Sorensen, K. P., Helbig, K. L., Lessel, D., Abou Jamra, R. De novo variants in GRIA4 lead to intellectual disability with or without seizures and gait abnormalities. Am. J. Hum. Genet. 101: 1013-1020, 2017. [PubMed: 29220673] [Full Text: https://doi.org/10.1016/j.ajhg.2017.11.004]
McNamara, J. O., Eubanks, J. H., McPherson, J. D., Wasmuth, J. J., Evans, G. A., Heinemann, S. F. Chromosomal localization of human glutamate receptor genes. J. Neurosci. 12: 2555-2562, 1992. [PubMed: 1319477] [Full Text: http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=1319477]
Ouardouz, M., Coderre, E., Zamponi, G. W., Hameed, S., Yin, X., Trapp, B. D., Stys, P. K. Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors. Ann. Neurol. 65: 160-166, 2009. [PubMed: 19224531] [Full Text: https://doi.org/10.1002/ana.21539]
Saab, A. S., Neumeyer, A., Jahn, H. M., Cupido, A., Simek, A. A. M., Boele, H.-J., Scheller, A., Le Meur, K., Gotz, M., Monyer, H., Sprengel, R., Rubio, M. E., Deitmer, J. W., De Zeeuw, C. I., Kirchhoff, F. Bergmann glial AMPA receptors are required for fine motor coordination. Science 337: 749-753, 2012. [PubMed: 22767895] [Full Text: https://doi.org/10.1126/science.1221140]
Sommer, B., Keinanen, K., Verdoorn, T. A., Wisden, W., Burnashev, N., Herb, A., Kohler, M., Takagi, T., Sakmann, B., Seeburg, P. H. Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249: 1580-1585, 1990. [PubMed: 1699275] [Full Text: https://doi.org/10.1126/science.1699275]