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RAG1
recombination activating 1
The RAG1 gene provides instructions for a protein crucial in the development and function of the immune system, particularly in enabling immune cells to recognise a wide array of foreign invaders. RAG1 is essential for generating diversity in immune cells (B and T lymphocytes), a process called V(D)J recombination.
RAG1 is located on the short (p) arm of chromosome 11, at band 11p12. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The RAG1 gene, also known as recombination activating 1, encodes a protein that plays a fundamental role in the adaptive immune system. This protein is part of the RAG complex, which is critical for creating the vast diversity of antibodies and T-cell receptors needed to identify and neutralise a wide range of pathogens. Inherited changes in the RAG1 gene can impair this process, leading to severe immunodeficiency conditions where the body struggles to fight off infections.
What the gene does
The RAG1 protein is a key component of the RAG complex, which is active within B and T lymphocytes - specialised immune cells. This complex facilitates V(D)J recombination, a crucial process for immune diversity. During V(D)J recombination, the RAG complex binds to specific DNA sequences, known as recombination signal sequences (RSS), adjacent to variable (V), diversity (D), and joining (J) gene segments. It then makes precise cuts in the DNA, allowing these segments to be rearranged in numerous combinations. This rearrangement ensures that B cells and T cells can produce a diverse repertoire of receptors, enabling them to recognise a broad spectrum of foreign antigens and effectively protect the body from infection.
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Chromosome location
The RAG1 gene is situated on chromosome 11, specifically at band 11p12. This genomic location houses the genetic instructions necessary for the RAG1 protein's synthesis, which is comprised of 1043 amino acids.
Protein structure
The RAG1 protein contains several distinct functional domains. The N-terminal region, spanning amino acids 1-288, is involved in interaction with importin alpha-1. A disordered region is found between amino acids 40-80. The protein also features a RING-type zinc finger from amino acids 293-332 and a RAG1-type zinc finger from amino acids 354-383. Additionally, a central NBD (DNA binding) domain is located from amino acids 392-459, which is crucial for its function in DNA rearrangement.
Key variants
Genetic variations within the RAG1 gene can influence its function. Many types of variants have been identified, including single nucleotide changes, insertions, and deletions, which can affect the protein's structure or expression. These variants can lead to a spectrum of clinical outcomes, depending on their impact on the RAG1 protein's ability to facilitate V(D)J recombination.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in the RAG1 gene are associated with various immune system disorders, collectively known as immunodeficiencies. Notably, at least 70 different variants have been linked to Omenn syndrome, a severe form of combined immunodeficiency (SCID). SCID is characterised by a near-total absence of immune protection, leaving individuals highly vulnerable to infections. Other RAG1 mutations can also cause SCID, often leading to severe recurrent infections from infancy that can be life-threatening.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic RAG1 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
The RAG1 gene is included in several NHS England Genomic Medicine Service approved 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).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the RAG1 gene?
The RAG1 gene provides instructions for a protein that is essential for V(D)J recombination. This process allows immune cells (B and T lymphocytes) to generate diverse receptors, enabling them to recognise and combat a wide range of pathogens.
What conditions are associated with RAG1 gene variants?
Variants in the RAG1 gene are primarily associated with severe combined immunodeficiency (SCID) disorders, including Omenn syndrome. These conditions lead to a compromised immune system and increased susceptibility to infections.
Is the RAG1 gene part of any NHS genetic testing panels?
Yes, RAG1 is included in several NHS England Genomic Medicine Service panels, such as those for primary immunodeficiency, gastrointestinal disorders, and rare inflammatory skin disorders, reflecting its clinical significance.
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