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ADGRG1
adhesion G protein-coupled receptor G1
The ADGRG1 gene encodes an adhesion G protein-coupled receptor vital for cell adhesion, cell migration, and the normal development of the brain, particularly the cerebral cortex. The ADGRG1 gene provides instructions for creating an adhesion G protein-coupled receptor.
ADGRG1 is located on the long (q) arm of chromosome 16, at band 16q21. Arm ratio per GRCh38 - banding schematic.
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Overview
The ADGRG1 gene, also known as GPR56, is responsible for producing an adhesion G protein-coupled receptor. This type of protein is embedded within cell membranes, where it acts as a receiver, relaying signals from outside the cell to its interior. This signalling mechanism is essential for various biological processes, including proper cell adhesion and migration.
The ADGRG1 protein is particularly important for the normal development and function of the brain. It is expressed in numerous body tissues and also appears to have roles in immune system function and the reproductive system.
What the gene does
The protein encoded by the ADGRG1 gene functions as a G protein-coupled receptor, a class of proteins involved in transmitting chemical signals across cell membranes. Research suggests that ADGRG1 signalling is crucial for cell adhesion, the process by which cells attach to one another, and cell migration, which is the movement of cells to specific locations.
In the brain, ADGRG1 plays a significant role in the growth and migration of neurons, particularly in the cerebral cortex, the outer layer responsible for sensation, movement, thought, and memory. It also contributes to the development and repair of myelin, the protective sheath around nerve fibres that enables efficient nerve impulse transmission.
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Chromosome location
The ADGRG1 gene is located on chromosome 16 at position 16q21. This specifies its precise address on the long arm of chromosome 16. The gene provides instructions for a protein that is 693 amino acids in length.
Protein structure
The ADGRG1 protein is composed of several key regions that contribute to its function. The GAIN-B domain spans amino acids 224-395 and is involved in protein maturation. Within this, the GPS (G protein-coupled receptor proteolytic site) region, from amino acids 346-395, is where the protein undergoes autoproteolytic cleavage. The Stachel region, located from amino acids 384-397, is believed to be important for activating the receptor. Additionally, a Disordered region is found towards the C-terminus, from amino acids 670-693.
Key variants
Variants within the ADGRG1 gene can alter the protein's structure or function, potentially impacting its crucial roles in cell signalling, adhesion, and migration. Such genetic changes may lead to various health implications, particularly affecting brain development. The clinical consequences of ADGRG1 variants can vary depending on the specific alteration.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1012C>T | p.Gln338Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.10C>T | p.Gln4Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.1131C>A | p.Cys377Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.113G>A | p.Arg38Gln | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1158_1162del | p.Val387fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.1216del | p.Leu406fs | Pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.1281C>A | p.Cys427Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.1384del | p.Ala461_Leu462insTer | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1408C>T | p.Arg470Ter | Pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
c.1457G>A | p.Trp486Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bilateral frontoparietal polymicrogyria |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ADGRG1 gene have been associated with several inherited conditions, primarily those affecting brain development. One notable condition is polymicrogyria, specifically a severe form known as bilateral frontoparietal polymicrogyria (BFPP). This condition is characterised by an abnormal number of small folds on the brain's surface.
No disease links recorded for this gene in our reference set.
UK clinical status
The ADGRG1 gene is included in several NHS Genomic Medicine Service national test panels. These panels cover conditions such as Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, and Malformations of cortical development. Its presence on these panels indicates its recognised clinical significance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ADGRG1 gene?
The ADGRG1 gene provides instructions for an adhesion G protein-coupled receptor that plays a critical role in cell adhesion, cell migration, and chemical signalling between cells. It is particularly important for normal brain development.
What conditions are associated with variants in ADGRG1?
Pathogenic variants in the ADGRG1 gene are associated with conditions primarily affecting brain development, including polymicrogyria, especially bilateral frontoparietal polymicrogyria (BFPP), which involves abnormal brain folding.
Where is the ADGRG1 gene located?
The ADGRG1 gene is located on chromosome 16, specifically at the 16q21 band. This chromosomal location helps in its identification and study within the human genome.
References
- Ke N, Ma H, Diedrich G. Biochemical characterization of genetic mutations of GPR56 in patients with bilateral frontoparietal polymicrogyria (BFPP). Biochemical and biophysical research communications. 2008. PMID: 18042463
- Iguchi T, Sakata K, Yoshizaki K. Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G alpha 12/13 and Rho pathway. The Journal of biological chemistry. 2008. PMID: 18378689
- Li S, Jin Z, Koirala S. GPR56 regulates pial basement membrane integrity and cortical lamination. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008. PMID: 18509043
- Ke N, Sundaram R, Liu G. Orphan G protein-coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway. Molecular cancer therapeutics. 2007. PMID: 17575113
- Jin Z, Tietjen I, Bu L. Disease-associated mutations affect GPR56 protein trafficking and cell surface expression. Human molecular genetics. 2007. PMID: 17576745
- Xu L, Begum S, Hearn JD. GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2006. PMID: 16757564
- Shashidhar S, Lorente G, Nagavarapu U. GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene. 2005. PMID: 15674329
- Piao X, Hill RS, Bodell A. G protein-coupled receptor-dependent development of human frontal cortex. Science (New York, N.Y.). 2004. PMID: 15044805