Alternative titles; symbols
HGNC Approved Gene Symbol: GRIK2
Cytogenetic location: 6q16.3 Genomic coordinates (GRCh38): 6:101,393,708-102,070,083 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q16.3 | Intellectual developmental disorder, autosomal recessive 6 | 611092 | Autosomal recessive | 3 |
| Neurodevelopmental disorder with impaired language and ataxia and with or without seizures | 619580 | Autosomal dominant | 3 |
The GRIK2 gene encodes the kainate receptor (KAR) subunit GluK2. KARs are ionotropic transmembrane channels activated by the neurotransmitter glutamate; they play an important role in neural development and central nervous system function (summary by Guzman et al., 2017).
Glutamate receptors mediate most excitatory neurotransmission in the brain, and molecular cloning studies have revealed several distinct families. Paschen et al. (1994) isolated a cDNA clone for the human glutamate receptor-6 kainate-preferring receptor. The clone showed a very high sequence similarity with that of the rat, except for a part of the 3-prime untranslated region in which there was a TAA triplet repeat. Northern analysis showed expression in both human cerebral and cerebellar cortices. The length of the TAA triplet repeat was polymorphic, with at least 4 alleles and an observed heterozygosity of about 45%.
Paschen et al. (1994) demonstrated RNA editing, posttranscriptional change of the sequence at the mRNA level, in human GLUR2 and GLUR6, as had previously been demonstrated in rats. A CAG, coding for glutamine within the putative second transmembrane domain of GLUR2, is changed to CGG, coding for arginine in the mRNA sequence. As in the rat, the GLUR2 subunit mRNA is completely edited in human brain. However, GLUR6 is only 10% edited in the corpus callosum and 90% edited in the gray matter.
Kainate receptors alter the excitability of mossy fiber axons and have been reported to play a role in the induction of long-term potentiation (LTP) at mossy fiber synapses in the hippocampus. Contractor et al. (2001) investigated short- and long-term facilitation of mossy fiber synaptic transmission in kainate receptor knockout mice. Contractor et al. (2001) found that LTP was reduced in mice lacking the GLUR6, but not the GLUR5 (138245), kainate receptor subunit. Additionally, short-term synaptic facilitation was impaired in Glur6 knockout mice, suggesting that kainate receptors act as presynaptic autoreceptors on mossy fiber terminals to facilitate synaptic transmission. Contractor et al. (2001) concluded that their data demonstrate that kainate receptors containing the GLUR6 subunit are important modulators of mossy fiber synaptic strength.
Martin et al. (2007) reported that in rat hippocampal neurons multiple sumoylation targets are present at synapses and demonstrated that the kainate receptor subunit GluR6 is a SUMO substrate. Sumoylation of GluR6 regulated endocytosis of the kainate receptor and modified synaptic transmission. GluR6 exhibited low levels of sumoylation under resting conditions and was rapidly sumoylated in response to a kainate but not an N-methyl-D-aspartate (NMDA) treatment. Reducing GluR6 sumoylation using the SUMO-specific isopeptidase SENP-1 prevented kainate-evoked endocytosis of the kainate receptor. Furthermore, a mutated non-sumoylatable form of GluR6 was not endocytosed in response to kainate in COS-7 cells. Consistent with this, electrophysiologic recordings in hippocampal slices demonstrated that kainate receptor-mediated excitatory postsynaptic currents were decreased by sumoylation and enhanced by desumoylation. Martin et al. (2007) concluded that their data revealed a previously unsuspected role for SUMO in the regulation of synaptic function.
Ouardouz et al. (2009) demonstrated that myelinated axons from rat spinal cord express functional GluR6-containing kainate receptors capable of mediating a deleterious axonal calcium increase from both extracellular and intraaxonal stores, resulting in white matter injury. The intracellular calcium release was dependent on L-type calcium channel (see 114205) activation. Immunohistochemical studies showed GluR6/GluR7 (GRIK3; 138243) clusters on the axolemma colocalized with Nos1 (163731) and L-type calcium channels, and GluR6 was functionally associated with Nos1.
Motazacker et al. (2007) determined that the GRIK2 gene comprises 16 exons.
Using PCR analysis of rodent/human monochromosomal cell lines, Paschen et al. (1994) assigned the GRIK2 gene to chromosome 6.
Huntington Disease Pathogenesis
In a sample of 293 patients with Huntington disease (HD; 143100), Rubinsztein et al. (1997) found that CAG repeats accounted for 69% of the variance of age of onset when they used the most parsimonious model relating the logarithm of age of onset to a function of CAG-repeat number. Seeking other familial factors, they examined a number of candidate loci: the CAG-repeat number on the normal chromosome, the delta-2642 polymorphism in the HD gene, and apolipoprotein E genotypes did not affect the age of onset of HD. Excitotoxicity has been a favored mechanism to explain cell death in HD, particularly since intrastriatal injection of excitatory amino acids in animals creates HD-like pathology. Accordingly, Rubinsztein et al. (1997) investigated glutamate receptor-6. Of the variance in the age of onset of HD that was not accounted for by the CAG repeats, 13% could be attributed to GRIK2 genotype variation. The data thus implicated glutamate receptor-6-mediated excitotoxicity in the pathogenesis of HD and pointed to the potential importance of this process in other polyglutamine repeat expansion diseases.
Intellectual Developmental Disorder 6, Autosomal Recessive
In affected members of a consanguineous Iranian family, Motazacker et al. (2007) identified a homozygous complex mutation in the GRIK2 gene (138244.0001) as the cause of nonsyndromic moderate to severe autosomal recessive intellectual developmental disorder-6 (MRT6; 611092).
In 2 adult sibs, born of consanguineous parents, with MRT6, Cordoba et al. (2015) identified a homozygous truncating mutation in the GRIK2 gene (R198X; 138244.0002). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The patients had delayed development from birth, cognitive impairment, and well-controlled seizures; one of the patients had movement abnormalities, including dystonia, tremor, and myoclonus.
Neurodevelopmental Disorder with Impaired Language and Ataxia and with or without Seizures
In a 10-year-old girl with neurodevelopmental disorder with impaired language and ataxia and without seizures (NEDLAS; 619580), Guzman et al. (2017) identified a de novo heterozygous missense mutation in the GRIK2 gene (A657T; 138244.0003). The mutation, which was found by trio-based exome sequencing, was not present in the ExAC or gnomAD databases. Voltage-clamp electrophysiologic studies in HEK293 cells transfected with the mutation showed slowed desensitization after glutamate application. Mutant A657T receptors showed increased mean currents compared to wildtype. Similar results were observed when coexpressed with heteromeric subunits, suggesting that the mutation causes constitutive activation and a gain-of-function effect with altered gating kinetics.
In 10 unrelated patients with NEDLAS with or without seizures, Stolz et al. (2021) identified 3 different de novo heterozygous missense mutations in the GRIK2 gene: A657T (138244.0003), T660K (138244.0004), and T660R (138244.0005). The mutations, which were found by exome sequencing, were not present in the gnomAD database. All occurred at conserved residues in the pore-forming M3 transmembrane domain that is critical for function. In vitro cellular studies showed that the levels of mutant protein expression at the surface membrane was decreased compared to controls. In vitro electrophysiologic studies of HEK293 cells transfected with the variants showed that they caused a slowing of deactivation and slower entry into desensitization compared to wildtype. Decreased mean amplitudes were also observed. These findings suggested that the mutations alter channel kinetics, resulting in a greater likelihood of channel opening and a tonic current in the presence of even low levels of glutamate. Stolz et al. (2021) postulated that the A657T mutation has a gain-of-function effect, whereas the T660 mutations may have a partial loss of function with subtle differences in KAR biophysical function; these differences may underlie clinical variability. The authors concluded that KAR signaling plays an important role in early development of the central nervous system.
In an Iranian family with autosomal recessive intellectual developmental disorder-6 (MRT6; 611092), Motazacker et al. (2007) identified a homozygous deletion removing exons 7 and 8 of the GRIK2 gene. Loss of these exons resulted in an in-frame deletion of 84 amino acids between residues 317 and 402, close to the first ligand-binding domain (S1) in the extracellular N-terminal region of the protein. Functional studies demonstrated complete loss of function of the mutant GRIK2 protein. Further studies to elucidate the full extent of the observed mutation showed that, in addition to the 120-kb deletion removing exons 7 and 8, the mutation comprised an inversion of approximately 80 kb including exons 9, 10, and 11, in combination with a deletion of approximately 20 kb of intron 11. Motazacker et al. (2007) predicted that at the protein level this mutation could be expected to result in the loss not only of the first ligand-binding domain but also of the adjacent transmembrane domain and the putative pore loop of GRIK2.
In 2 sibs, born of consanguineous parents, with autosomal recessive intellectual developmental disorder-6 (MRT; 611092), Cordoba et al. (2015) identified a homozygous mutation in the GRIK2 gene, resulting in an arg198-to-ter (R198X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In a 10-year-old girl with neurodevelopmental disorder with impaired language and ataxia who did not have seizures (NEDLAS; 619580), Guzman et al. (2017) identified a de novo heterozygous c.1969G-A transition in the GRIK2 gene, resulting in an ala657-to-thr (A657T) substitution at a highly conserved residue within the pore-forming M3 transmembrane domain. The mutation, which was found by trio-based exome sequencing, was not present in the ExAC or gnomAD databases. Voltage-clamp electrophysiologic studies in HEK293 cells transfected with the mutation showed slowed desensitization after glutamate application. Mutant A657T receptors showed increased mean currents compared to wildtype, and similar results were observed when coexpressed with heteromeric subunits, suggesting that the mutation causes constitutive activation and a gain-of-function effect with altered gating kinetics.
Stolz et al. (2021) identified a de novo heterozygous c.1969G-A transition (chr6.101,928,516G-A, GRCh38) in the GRIK1 gene, resulting in an ala657-to-thr (A657T) substitution in 5 unrelated patients with NEDLAS without seizures. The mutation was found by exome sequencing. In vitro functional expression studies indicated that the mutation causes profound slowing of deactivation compared to wildtype, consistent with a gain-of-function effect.
In 3 unrelated patients with neurodevelopmental disorder with impaired language, ataxia, and seizures (NEDLAS; 619580), Stolz et al. (2021) identified a de novo heterozygous c.1979C-A transversion (chr6.101,928,526C-A, GRCh38) in the GRIK2 gene, resulting in a thr660-to-lys (T660K) substitution at a conserved residue in the M3 transmembrane domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies indicated that the mutation caused profound slowing of channel deactivation and constitutive tonic current activation compared to wildtype, indicating altered channel gating kinetics.
In 2 unrelated patients with neurodevelopmental disorder with impaired language, ataxia, and seizures (NEDLAS; 619580), Stolz et al. (2021) identified a de novo heterozygous c.1979C-G transversion (chr6.102,376,401C-G, GRCh38) in the GRIK2 gene, resulting in a thr660-to-arg (T660R) substitution at a conserved residue in the M3 transmembrane domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies indicated that the mutation caused profound slowing of channel deactivation and constitutive tonic current activation compared to wildtype, indicating altered channel gating kinetics.
Contractor, A., Swanson, G., Heinemann, S. F. Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus. Neuron 29: 209-216, 2001. [PubMed: 11182092] [Full Text: https://doi.org/10.1016/s0896-6273(01)00191-x]
Cordoba, M., Rodriguez, S., Gonzalez Moron, D., Medina, N., Kauffman, M. A. Expanding the spectrum of Grik2 mutations: intellectual disability, behavioural disorder, epilepsy and dystonia. (Letter) Clin. Genet. 87: 293-295, 2015. [PubMed: 25039795] [Full Text: https://doi.org/10.1111/cge.12423]
Guzman, Y. F., Ramsey, K., Stolz, J. R., Craig, D. W., Huentelman M. J., Narayanan, V., Swanson, G. T. A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits. Neurol. Genet. 3: e129, 2017. [PubMed: 28180184] [Full Text: https://doi.org/10.1212/NXG.0000000000000129]
Martin, S., Nishimune, A., Mellor, J. R., Henley, J. M. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447: 321-325, 2007. [PubMed: 17486098] [Full Text: https://doi.org/10.1038/nature05736]
Motazacker, M. M., Rost, B. R., Hucho, T., Garshasbi, M., Kahrizi, K., Ullmann, B., Abedini, S. S., Nieh, S. E., Amini, S. H., Goswami, C., Tzschach, A., Jensen, L. R., Schmitz, D., Ropers, H. H., Najmabadi, H., Kuss, A. W. A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am. J. Hum. Genet. 81: 792-798, 2007. [PubMed: 17847003] [Full Text: https://doi.org/10.1086/521275]
Ouardouz, M., Coderre, E., Basak, A., Chen, A., Zamponi, G. W., Hameed, S., Rehak, R., Yin, X., Trapp, B. D., Stys, P. K. Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors. Ann. Neurol. 65: 151-159, 2009. [PubMed: 19224535] [Full Text: https://doi.org/10.1002/ana.21533]
Paschen, W., Blackstone, C. D., Huganir, R. L., Ross, C. A. Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment. Genomics 20: 435-440, 1994. [PubMed: 8034316] [Full Text: https://doi.org/10.1006/geno.1994.1198]
Paschen, W., Hedreen, J. C., Ross, C. A. RNA editing of the glutamate receptor subunits GluR2 and GluR6 in human brain tissue. J. Neurochem. 63: 1596-1602, 1994. [PubMed: 7523595] [Full Text: https://doi.org/10.1046/j.1471-4159.1994.63051596.x]
Rubinsztein, D. C., Leggo, J., Chiano, M., Dodge, A., Norbury, G., Rosser, E., Craufurd, D. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc. Nat. Acad. Sci. 94: 3872-3876, 1997. [PubMed: 9108071] [Full Text: https://doi.org/10.1073/pnas.94.8.3872]
Stolz, J. R., Foote, K. M., Veenstra-Knol, H. E., Pfundt, R., ten Broeke, S. W., de Leeuw, N., Roht, L., Pajusalu, S., Part, R., Rebane, I., Ounap, K., Stark, Z., and 27 others. Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders Am. J. Hum. Genet. 108: 1692-1709, 2021. Note: Erratum: Am. J. Hum. Genet. 108: 2206 only, 2021. [PubMed: 34375587] [Full Text: https://doi.org/10.1016/j.ajhg.2021.07.007]