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ADGRG1
adhesion G protein-coupled receptor G1
The ADGRG1 gene provides instructions for a protein that acts as a G protein-coupled receptor, essential for normal brain development, particularly nerve cell migration and myelination. The ADGRG1 gene encodes adhesion G protein-coupled receptor G1, a protein located in cell membranes.
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 the adhesion G protein-coupled receptor G1. This protein is integral to cell membranes, where it facilitates communication by relaying signals from the cell's exterior to its interior. Research indicates that the ADGRG1 protein is particularly important for the normal development of the brain, influencing processes like cell adhesion and migration.
Beyond its significant role in the brain, the ADGRG1 protein is active in various body tissues. It is thought to contribute to the function of the immune system and the development of the reproductive system.
What the gene does
The ADGRG1 gene produces a G protein-coupled receptor, a type of protein embedded within the outer membrane of cells. These receptors are crucial for cellular communication, acting as intermediaries that transmit chemical signals from the external environment into the cell's interior. Studies suggest that ADGRG1 protein signalling is fundamental for cell adhesion, the process by which cells attach to one another.
This adhesive property may be vital for proper cell movement, or migration, particularly during development. In the brain, the ADGRG1 protein is essential for the normal growth and migration of nerve cells (neurons) within the cerebral cortex, the brain's outer layer involved in sensation, movement, thought, and memory. Additionally, the ADGRG1 protein contributes to the development and repair of myelin, the protective sheath around nerve fibres that enables rapid nerve impulse transmission.
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Chromosome location
The ADGRG1 gene is situated on chromosome 16. Specifically, its location is designated as 16q21, which refers to the long (q) arm of chromosome 16 at position 21.
Protein structure
The ADGRG1 protein is composed of 693 amino acids. It features several distinct regions and domains crucial for its function. The GAIN-B domain spans amino acids 224-395. Within this, a GPS region is found from amino acids 346-395. A Stachel region is located between amino acids 384-397, and a Disordered region is present at the C-terminus, from amino acids 670-693.
Key variants
Genetic variations within the ADGRG1 gene can alter the protein's structure and function. Such variations, known as pathogenic variants, may lead to impaired protein activity or production. The specific impact of a variant often depends on its location within the gene and how it changes the resulting protein.
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 are associated with specific neurodevelopmental conditions. These include a severe form of polymicrogyria, known as bilateral frontoparietal polymicrogyria (BFPP). Polymicrogyria is characterised by an excessive number of small folds on the brain's surface, with BFPP affecting both sides of the brain.
No disease links recorded for this gene in our reference set.
UK clinical status
The ADGRG1 gene is assessed within several UK NHS Genomic Medicine Service pathways. It is currently categorised as 'green' on PanelApp for conditions such as Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, and Malformations of cortical development, indicating strong evidence for its involvement in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ADGRG1 protein?
The ADGRG1 protein functions as a G protein-coupled receptor, primarily involved in relaying chemical signals across cell membranes. It is crucial for cell adhesion and migration, playing a significant role in normal brain development, particularly in nerve cell growth and myelin formation.
What is polymicrogyria?
Polymicrogyria is a brain malformation characterised by an abnormal number of small, irregular folds on the surface of the brain. When caused by ADGRG1 variants, it often presents as bilateral frontoparietal polymicrogyria (BFPP), affecting both sides of the brain.
Is ADGRG1 only important in the brain?
While the ADGRG1 protein is most extensively studied in the brain due to its critical role in neurodevelopment, it is active in many other tissues throughout the body. Research suggests it may also contribute to immune system function and the development of the reproductive system.
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