Alternative titles; symbols
HGNC Approved Gene Symbol: GPRC5B
Cytogenetic location: 16p12.3 Genomic coordinates (GRCh38) : 16:19,856,691-19,885,634 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.3 | Megalencephalic leukoencephalopathy with subcortical cysts 3 | 620447 | Autosomal dominant | 3 |
G protein-coupled receptors (GPCRs) share a common structure of 7 transmembrane domains, an extracellular N-terminal domain, an intracellular C-terminal domain, and several conserved residues. Family C of the GPCR superfamily, which includes GPRC5B, consists of metabotropic glutamate receptor-like proteins (e.g., GRM2; 604099) (summary by Brauner-Osborne and Krogsgaard-Larsen, 2000).
By searching sequence databases for metabotropic glutamate receptor homologs, Robbins et al. (2000) and Brauner-Osborne and Krogsgaard-Larsen (2000) identified cDNAs encoding GPRC5B, which Robbins et al. (2000) called RAIG2. Robbins et al. (2000) predicted that GPRC5B is a 403-amino acid protein, while Brauner-Osborne and Krogsgaard-Larsen (2000) predicted the use of a different start codon that results in a 395-amino acid protein encoded by 3 exons. The GPRC5B protein contains 7 predicted transmembrane helices and conserved cysteines characteristic of GPCRs. It also contains a predicted signal peptide and a potential N-glycosylation site. Robbins et al. (2000) reported that GPRC5B shares 43% and 38% amino acid identity with GPRC5C (605949) and RAIG1 (RAI3; 604138), respectively. Brauner-Osborne and Krogsgaard-Larsen (2000) assigned GPRC5B to family C, group 5, of the GPCR superfamily. In contrast to other members of family C, GPRC5B has a short N-terminal domain, and Brauner-Osborne and Krogsgaard-Larsen (2000) hypothesized that it may represent a novel subgroup of family C receptors. Using a PCR-based expression analysis, Robbins et al. (2000) detected GPRC5B transcripts at highest levels in brain, with most abundant expression in corpus callosum, caudate nucleus, putamen, substantia nigra, thalamus, hippocampus, and spinal cord. Using RT-PCR, Brauner-Osborne and Krogsgaard-Larsen (2000) detected widespread expression of GPRC5B, with highest levels in kidney, pancreas, and testis, and medium levels in brain, heart, prostate, small intestine, and spleen. After retinoic acid treatment, Robbins et al. (2000) observed induction of GPRC5B expression in some human transformed cell lines. Using transient transfection experiments, Robbins et al. (2000) detected GPRC5B expression on the cell surface.
In human brain tissue, Passchier et al. (2023) found expression of the GPRC5B gene in astrocyte cell bodies in white matter. GPRC5B showed clear perivascular staining, as well as localization to the glia limitans and in ependymal cells, but not in neurons. Electron microscopy showed membranous labeling of GPRC5B in the perivascular region in astrocyte endfeet, confirming proximity to MLC1 (605908), GlialCAM (HEPACAM; 611642), AQP4 (600308), and other proteins involved in astrocyte ion and water homeostasis. Membranous labeling of GPRC5B was also observed in endothelial cells and pericytes; lymphocytes showed intracellular and membranous GPRC5B labeling.
Using STS analysis, Robbins et al. (2000) mapped the GPRC5B gene to 16p12.3-p12.1. Brauner-Osborne and Krogsgaard-Larsen (2000) identified the GPRC5B sequence in a BAC clone mapped to 16p12.
In 3 unrelated patients (P1-P3) with megalencephalic leukoencephalopathy with subcortical cysts-3 (MLC3; 620447), Passchier et al. (2023) identified 2 different de novo heterozygous 3-bp in-frame duplications in the GPRC5B gene (605948.0001 and 605948.0002). Both mutations occurred in the fourth transmembrane protein domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed a strong increase in GPRC5B levels compared to controls. MLC1 (605908) levels were similar to controls, but levels of the cation channel TRPV4 (605427) were strongly decreased. In vitro functional studies showed that regulatory volume decrease (RVD) in patient lymphoblasts was reduced following swelling compared to controls. These findings indicated disturbed volume regulation in patient lymphoblasts, potentially due to increased GPRC5B expression. Overexpression of mutant and wildtype GPRC5B in human astrocytoma cells increased volume-regulated anion channel (VRAC) function to similar degrees. Passchier et al. (2023) suggested that increased GPRC5B expression causes chronic white matter edema by disrupting fine tuning of the essential volume-regulating channels VRAC and TRPV4.
In 2 unrelated patients (P1 and P2) with megalencephalic leukoencephalopathy with subcortical cysts-3 (MLC3; 620447), Passchier et al. (2023) identified a de novo heterozygous 3-bp in-frame duplication (c.526_528dup, NM_016235.2) in the GPRC5B gene, resulting in the duplication of residue ile176 (Ile176dup) in the fourth transmembrane protein domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed a strong increase in GPRC5B levels compared to controls. This increase was accompanied by impaired regulatory volume decrease (RVD) in patient lymphoblasts following swelling compared to controls.
In a patient (P3) with megalencephalic leukoencephalopathy with subcortical cysts-3 (MLC3; 620447), Passchier et al. (2023) identified a de novo heterozygous 3-bp in-frame duplication (c.528_530dup, NM_016235.2) in the GPRC5B gene, resulting in the duplication of residue ala177 (Ala177dup) in the fourth transmembrane protein domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed a strong increase in GPRC5B levels compared to controls. This increase was accompanied by impaired regulatory volume decrease (RVD) in patient lymphoblasts following swelling compared to controls.
Brauner-Osborne, H., Krogsgaard-Larsen, P. Sequence and expression pattern of a novel human orphan G-protein-coupled receptor, GPRC5B, a family C receptor with a short amino-terminal domain. Genomics 65: 121-128, 2000. [PubMed: 10783259] [Full Text: https://doi.org/10.1006/geno.2000.6164]
Passchier, E. M. J., Kerst, S., Brouwers, E., Hamilton, E. M. C., Bisseling, Q., Bugiani, M., Waisfisz, Q., Kitchen, P., Unger, L., Breur, M., Hoogterp, L., de Vries, S. I., and 12 others. Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema. Brain 146: 3444-3454, 2023. [PubMed: 37143309] [Full Text: https://doi.org/10.1093/brain/awad146]
Robbins, M. J., Michalovich, D., Hill, J., Calver, A. R., Medhurst, A. D., Gloger, I., Sims, M., Middlemiss, D. N., Pangalos, M. N. Molecular cloning and characterization of two novel retinoic acid-inducible orphan G-protein-coupled receptors (GPRC5B and GPRC5C). Genomics 67: 8-18, 2000. [PubMed: 10945465] [Full Text: https://doi.org/10.1006/geno.2000.6226]