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RAG2
recombination activating 2
The RAG2 gene provides instructions for a protein essential in developing a diverse and effective immune system, enabling the body to recognise and combat a wide range of pathogens. RAG2 is a vital gene involved in the complex process of V(D)J recombination within immune cells.
RAG2 is located on the short (p) arm of chromosome 11, at band 11p12. Arm ratio per GRCh38 - banding schematic.
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Overview
The RAG2 gene, or recombination activating 2, is fundamental to the adaptive immune system's proper function. It codes for a protein that is part of the RAG complex, which is critical for creating diverse B and T cell receptors. This diversity is essential for the immune system to recognise and respond effectively to numerous foreign invaders.
Disruptions in RAG2 function can lead to severe primary immunodeficiencies, characterised by a profound inability to fight off infections. Understanding the role of RAG2 is therefore important for diagnosing and potentially treating these life-threatening conditions.
What the gene does
The RAG2 protein is a key component of the RAG complex, which orchestrates V(D)J recombination in lymphocytes (B cells and T cells). This process involves rearranging variable (V), diversity (D), and joining (J) gene segments. These segments ultimately form the genes for immune proteins that recognise antigens.
Specifically, the RAG complex binds to recombination signal sequences (RSS) adjacent to V, D, or J segments. It then initiates precise cuts in the DNA, allowing these segments to be separated and rejoined in different combinations. This recombination generates a vast repertoire of unique antigen receptors, crucial for effective immunity. Without functional RAG2, lymphocytes cannot develop the necessary diversity to protect the body against various bacteria, viruses, and fungi.
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Chromosome location
The RAG2 gene is situated on chromosome 11, specifically at the p12 band. This chromosomal location indicates where the gene resides within the human genome. Its position is stable across individuals, forming part of the genetic blueprint that guides immune system development.
Protein structure
The RAG2 protein comprises 527 amino acids. Within its structure, specific functional regions have been identified. It features a Disordered region spanning amino acids 357 to 380, which typically implies flexibility and potential involvement in protein-protein interactions. Additionally, an atypical PHD-type zinc finger domain is located between amino acids 416 and 484, suggesting a role in chromatin binding or regulation of gene expression.
Key variants
Variants in the RAG2 gene can impact the protein's ability to facilitate V(D)J recombination, leading to diverse clinical presentations. These genetic changes can range from small alterations to larger deletions, affecting the quantity or function of the RAG2 protein. The severity of the resulting immune dysfunction often correlates with the impact of the specific variant on protein activity.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Mutations in the RAG2 gene are associated with various forms of severe combined immunodeficiency (SCID), an umbrella term for conditions causing near-total lack of immune protection. One specific condition linked to RAG2 variants is Omenn syndrome, which is a type of SCID characterised by reduced ability to fight infections. Other disorders include forms of SCID with few or absent B and T cells, leading to recurrent and persistent infections typically fatal within the first year of life if untreated.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic RAG2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the RAG2 gene is included on several NHS Genomic Medicine Service national test panels. These include panels for COVID-19 research, gastrointestinal epithelial barrier disorders, infantile enterocolitis & monogenic inflammatory bowel disease, primary immunodeficiency or monogenic inflammatory bowel disease (R15), rare genetic inflammatory skin disorders (R332), and respiratory ciliopathies including non-CF bronchiectasis (R189). Its presence on these panels highlights its established clinical relevance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the RAG2 gene?
The RAG2 gene is essential for V(D)J recombination, a process that shuffles gene segments in immune cells (B and T cells). This creates a diverse range of immune receptors, enabling the body to recognise and fight various infections.
What happens if the RAG2 gene has a variant?
Variants in the RAG2 gene can disrupt its function, leading to a severely compromised immune system. This can result in conditions like Omenn syndrome or other forms of severe combined immunodeficiency (SCID), where the body struggles to fight off infections.
Is RAG2 associated with other conditions?
Beyond Omenn syndrome, RAG2 gene variants can cause other forms of severe combined immunodeficiency. These typically involve a significant reduction or absence of functional B and T cells, making individuals highly vulnerable to recurrent and severe infections.
References
- Carmona LM, Schatz DG. New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination. The FEBS journal. 2017. PMID: 27973733
- Bai X, Liu J, Zhang Z. Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome. Immunologic research. 2016. PMID: 26476733
- Notarangelo LD, Kim MS, Walter JE. Human RAG mutations: biochemistry and clinical implications. Nature reviews. Immunology. 2016. PMID: 26996199
- Ru H, Chambers MG, Fu TM. Molecular Mechanism of V(D)J Recombination from Synaptic RAG1-RAG2 Complex Structures. Cell. 2015. PMID: 26548953
- Cassani B, Poliani PL, Moratto D. Defect of regulatory T cells in patients with Omenn syndrome. The Journal of allergy and clinical immunology. 2010. PMID: 20109747
- Somech R, Simon AJ, Lev A. Reduced central tolerance in Omenn syndrome leads to immature self-reactive oligoclonal T cells. The Journal of allergy and clinical immunology. 2009. PMID: 19767069