HGNC Approved Gene Symbol: GRID2
Cytogenetic location: 4q22.1-q22.2 Genomic coordinates (GRCh38): 4:92,303,966-93,810,456 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q22.1-q22.2 | Spinocerebellar ataxia, autosomal recessive 18 | 616204 | Autosomal recessive | 3 |
GRID2 is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors. The GRID2 gene encodes the glutamate receptor channel delta-2 subunit, thought to be selectively expressed in cerebellar Purkinje cells (Takayama et al., 1995).
Araki et al. (1993) identified a gene for the delta-2 subunit of the mouse glutamate receptor channel (Grid2) by screening brain cDNA libraries with a delta-1 subunit probe. The Grid2 predicted 1,007-amino acid protein contains a putative 15-amino acid N-terminal signal sequence and 4 putative transmembrane domains. Mouse Grid2 mRNA is expressed selectively in cerebellar Purkinje cells.
Hu et al. (1998) isolated the human GRID2 gene by probing a cerebellar cDNA library with the mouse cDNA. The predicted 1,007-amino acid human protein is 97% identical to that of mouse Grid2.
Hills et al. (2013) found expression of GRID2 in the molecular layer of the human cerebellum. GRID2 expression was found in puncta and aligned with parallel fiber-Purkinje cell synapses.
By radiation hybrid mapping and based on its inclusion in YACs covering that region, Hu et al. (1998) localized the human GRID2 gene to 4q22. This region is syntenic with mouse chromosome 6, to which Zuo et al. (1997) mapped the mouse Grid2 gene.
Takayama et al. (1995) investigated the localization of Grid2 in mouse Purkinje cells by immunohistochemistry. From results of electron microscopic analysis, they concluded that Grid2 was localized in the dendritic spines of the Purkinje cells. Landsend et al. (1997) used a high-resolution immunogold procedure to perform detailed studies of GRID2 localization within the rat cerebellar cortex. They concluded that GRID2 was expressed selectively at parallel fiber-Purkinje cell synapses.
Using homologous recombination in mice, Kashiwabuchi et al. (1995) generated a null allele of the Grid2 gene in which the exon encoding the putative transmembrane M3 segment was replaced with the neomycin transferase gene. Mice homozygous for the null allele showed severe ataxia, impairment in cerebellar long-term depression, and multiinnervation of Purkinje cells by climbing fibers. Kashiwabuchi et al. (1995) concluded that the delta-2 subunit plays important roles in motor coordination, formation of parallel fiber-Purkinje cell synapses and climbing fiber-Purkinje cell synapses, and long-term depression of parallel fiber-Purkinje cell synaptic transmission.
Using a yeast 2-hybrid system to screen for proteins interacting with the C-terminal cytosolic tail of mouse Grid2, Yue et al. (2002) identified an isoform of Pist (606845), which they called nPist. Using coimmunoprecipitation and colocalization experiments, the authors demonstrated that interaction between Grid2 and nPist is specific and requires the C terminus of Grid2 and the nPist PDZ domain. They concluded that Grid2 forms a complex with nPist and Becn1 (604378) in cerebellar Purkinje cells in vivo.
Hirai et al. (2003) generated a specific antibody to the putative ligand-binding region of the delta-2 subunit of the glutamate receptor. Application of the antibody to cultured Purkinje cells attenuated synaptic transmission, induced postsynaptic AMPA receptor (see 138248) endocytosis, and abrogated long-term depression. Injection of the antibody into the subarachnoidal supracerebellar space of adult mice caused transient cerebellar dysfunction, such as ataxic gait. Hirai et al. (2003) concluded that Grid2 is involved in AMPA receptor trafficking and cerebellar function in adult mice.
Matsuda et al. (2010) found that Cbln1 (600432) binds directly to the N-terminal domain of the glutamate receptor delta-2 (Grid2). Grid2 expression by postsynaptic cells, combined with exogenously applied Cbln1, was necessary and sufficient to induce new synapses in vitro and in the adult cerebellum in vivo. Further, beads coated with recombinant Cbln1 directly induced presynaptic differentiation and indirectly caused clustering of postsynaptic molecules via Grid2. Matsuda et al. (2010) concluded that the Cbln1-Grid2 complex is a unique synaptic organizer that acts bidirectionally on both pre- and postsynaptic components in the cerebellum.
Autosomal Recessive Spinocerebellar Ataxia 18
In 3 patients from a consanguineous Turkish family with autosomal recessive spinocerebellar ataxia-18 (SCAR18; 616204), Utine et al. (2013) identified a homozygous deletion of exons 3 and 4 in the GRID2 gene (602368.0002). The deletion, which was found by genomewide array analysis and confirmed by PCR, segregated with the disorder in the family. Functional studies were not performed.
In 3 patients from a consanguineous Turkish family with SCAR18, Hills et al. (2013) identified a homozygous deletion in the GRID2 gene (602368.0003), resulting in a truncated protein. The mutation was found by a combination of linkage analysis, candidate gene investigation, and custom array CGH. A Mexican child with a similar disorder was compound heterozygous for 2 deletions within the GRID2 gene (602368.0004 and 602368.0005). Both Utine et al. (2013) and Hills et al. (2013) noted phenotypic similarities to the phenotype of mutant mice with homozygous deletions in the Grid2 gene (see ANIMAL MODEL).
Associations Pending Confirmation
Maier et al. (2014) identified a 276-kb deletion spanning the first exon of the GRID2 gene (602368.0001) in a 24-year-old patient with spastic paraplegia, ataxia, frontotemporal dementia, and lower motor neuron disease. This deletion was a de novo event. The authors suggested that this might be a form of Troyer syndrome (see 275900).
The semidominant neurologic mouse mutation 'lurcher' in heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Homozygous lurcher mice die shortly after birth because of massive loss of mid- and hindbrain neurons during late embryogenesis. Zuo et al. (1997) found that a point mutation in the Grid2 gene is responsible for the lurcher phenotype. They showed that lurcher is a gain-of-function mutation that yields a constitutively open channel. Zuo et al. (1997) proposed that the resulting constitutive inward current activates apoptotic neuronal death, leading to the massive neuronal loss in homozygous lurcher mice.
Lalouette et al. (1998) showed that mutations in the mouse Grid2 gene are responsible for at least 2 alleles of 'hotfoot' (ho), a recessive mouse mutant phenotype characterized by cerebellar ataxia associated with relatively mild abnormalities of the cerebellum. Using Northern blot and PCR analysis, they identified a 510-bp deletion in the ho(4J) allele and a 4-kb deletion in the ho(TgN371NRA) allele. Lalouette et al. (1998) hypothesized that each of the mutations results in loss of function because the hotfoot phenotype is similar to the Grid2 knockout phenotype (Kashiwabuchi et al., 1995).
Yue et al. (2002) hypothesized that in lurcher mice, the mutant Grid2 gene causes release of Pist and Becn1 from the normal Grid2/Pist/Becn1 complex, resulting in constitutive activation of the autophagy pathway and contributing to Purkinje cell death. They concluded that the Grid2 mutant allele expressed in lurcher mice, but not wildtype Grid2, can induce autophagy, a pathway for bulk degradation of subcellular constituents.
By analyzing lurcher/hotfoot heteroallelic mutant mice bearing only 1 copy of the lurcher allele and no wildtype Grid2, Selimi et al. (2003) found that autophagy and Purkinje cell death were independent of depolarization. Neural death appeared to be due to direct activation of autophagy by lurcher Grid2 receptors through the Grid2-nPist-Becn1 signaling pathway.
Hills et al. (2013) noted that the hotfoot mutant mouse has an in-frame deletion of exon 2, as found in a Mexican patient with SCAR18 (see 602368.0004). Using an infrared camera, Hills et al. (2013) observed that hotfoot mice had significantly larger spontaneous and random eye movements, indicating oculomotor dysfunction, compared to controls.
This variant is classified as a variant of unknown significance because its contribution to Troyer syndrome (see 275900) has not been confirmed.
In a 24-year-old man with spastic paraplegia, ataxia, frontotemporal dementia, and lower motor neuron disease, Maier et al. (2014) identified a 276-kb deletion encompassing the first exon of the GRID2 gene (chr4:92,981,313-93,256,907, GRCh37). This deletion was a de novo event. The authors noted the phenotypic similarity to Troyer syndrome and excluded mutations in the SPG20 gene (607111). The GRID2 mutation was identified by array CGH of the patient's entire genome and confirmed by quantitative PCR. Maier et al. (2014) noted the resemblance of the patient's phenotype to that of mouse models with Grid2 mutation.
In 3 patients from a consanguineous Turkish kindred with autosomal recessive spinocerebellar ataxia-18 (SCAR18; 616204), Utine et al. (2013) identified a homozygous 144-kb deletion on chromosome 4q22.2 (chr4:94,153,589-94,298,037) including exons 3 and 4 of the GRID2 gene. The deletion, which was found by genomewide array analysis and confirmed by PCR, segregated with the disorder in the family. Functional studies of the deletion were not performed.
In 3 affected patients from a consanguineous Turkish kindred (CH-4900) with SCAR18 (616204), Hills et al. (2013) identified a homozygous 37-kb deletion (chr:94,019,842-94,056,765, GRCh37) involving exon 4 of the GRID2 gene, predicted to result in a frameshift and premature termination (Asp177GlyfsTer5). The deletion, which was found by linkage analysis, candidate gene investigation, and custom array CGH, segregated with the disorder in the family. The deletion was confirmed by PCR analysis. Functional studies of the deletion were not performed.
In a Mexican girl (CH-5401) with SCAR18 (616204), Hills et al. (2013) identified compound heterozygous deletions within the GRID2 gene: a 50-kb deletion (chr4:93,481,110-93,531,257, GRCh37) involving exon 2 that was inherited from the unaffected mother, and a 335-kb de novo deletion (chr4:93,412,943-93,748,082, GRCh37; 602368.0005) including exon 2 on the paternal chromosome. The patient thus had biallelic deletion of exon 2, which is expected to result in an in-frame deletion of 52 residues (Gly30_Glu81del). The deletions were confirmed by PCR analysis. Functional studies of the deletions were not performed.
For discussion of the 335-kb deletion in the GRID2 gene that was found in compound heterozygous state in a patient with SCAR18 (616204) by Hills et al. (2013), see 602368.0004.
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Utine, G. E., Haliloglu, G., Salanci, B., Cetinkaya, A., Kiper, P. O., Alanay, Y., Aktas, D., Boduroglu, K., Alikasifoglu, M. A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy. J. Child Neurol. 28: 926-932, 2013. [PubMed: 23611888] [Full Text: https://doi.org/10.1177/0883073813484967]
Yue, Z., Horton, A., Bravin, M., DeJager, P. L., Selimi, F., Heintz, N. A novel protein complex linking the delta-2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron 35: 921-933, 2002. [PubMed: 12372286] [Full Text: https://doi.org/10.1016/s0896-6273(02)00861-9]
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