GRID2 and Associated Diseases
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Backgrounds of GRID2 Gene
GRID2 is an a16 exongene located on chromosome 4 and encodes for a protein called glutamate receptor D2 (GluRD2). It is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors, though it does not bind glutamate. GRID2 is mostly expressed in Purkinje cells (PCs), in dendritic spines, at the postsynaptic side of the synapses with parallel fibers (PFs) issued from granular cells. The GluRD2 general structure is similar to other iGluRs, with an extracellular ligand binding domain composed of 2 segments (S1 and S2), 4 transmembrane segments (M1-M4) of which M1, M3, and M4 are responsible for the channel pore formation, and 3 linkers (S1M1, M3S2, S2M4). GRID2 gene expression increases as development progress, reaching a constant expression level in adult mice, which is consistent with the gene expression profiles of other retinal genes.
Fig.1 Schematic of the gene GRID2 on chromosome 4q22.1-q22.2. (Hills, 2013)
Functions of GRID2 Gene
Studies in mice have shown that GRID2 is mainly expressed in Purkinje cells and is essential for synapse formation and organization. Furthermore, mice with homozygous disruption of GRID2 show ataxia and mild cerebellar hypoplasia. The GluRD2 protein is highly conserved between mice and humans. Its knock-out in mice is associated with ataxia due to a reduction of PF-PC synaptic contacts and long-term depression impairment. The GRID2 gene has been associated with neurological disorders, such as Parkinson's disease and cerebellar ataxia. GRID2 has also been shown to regulate long-term depression in the developing mouse cerebellum through its interaction with D-serine. GRID2 has dual roles in synaptic organization and regulation of synaptic communication and is essential for the development and function of the mouse cerebellum.
Expression of GRID2 in Diseases
The GRID2 gene is located in a common fragile locus of the genome, a region of high genomic instability that is associated with very large genes and deletions in cancer. GRID2 mutation/expression change is related to a variety of malignant tumors such as thyroid, stomach, breast, glioma, prostate cancer, and urothelial cancer. GRID2 deficiency may change the symbiotic state between the host and microbiota and affect the development of related diseases. The phenotype associated with defects in the GRID2 gene includes nystagmus, hypotonia, truncal ataxia, developmental delay, oculomotor apraxia, and coordination defect with cerebellar and pyramidal tract involvement, accompanied by progressive cerebellar atrophy on serial neuroimaging studies.
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Reference
- Hills, L.B.; et al. Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology. 2013, 81(16): 1378-1386.
