RAG1

Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene.[5]

RAG1
Identifiers
Aliases	RAG1, RAG-1, RNF74, recombination activating gene 1, recombination activating 1
External IDs	OMIM: 179615 MGI: 97848 HomoloGene: 387 GeneCards: RAG1
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p12 Start 36,510,709 bp[1] End 36,593,156 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 E2|2 53.88 cM Start 101,638,282 bp[2] End 101,649,501 bp[2]
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • protein homodimerization activity • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity • histone binding • zinc ion binding • metal ion binding • ubiquitin-protein transferase activity • GO:0001948 protein binding • catalytic activity • nuclease activity • endonuclease activity • hydrolase activity • transferase activity • identical protein binding • double-stranded DNA endodeoxyribonuclease activity Cellular component • nucleoplasm • cell nucleus • DNA recombinase complex • endodeoxyribonuclease complex Biological process • positive regulation of T cell differentiation • histone monoubiquitination • DNA recombination • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • adaptive immune response • T cell differentiation in thymus • nucleic acid phosphodiester bond hydrolysis • thymus development • negative regulation of thymocyte apoptotic process • T cell homeostasis • negative regulation of T cell apoptotic process • immune response • V(D)J recombination • pre-B cell allelic exclusion • B cell differentiation • metabolism • regulation of T cell differentiation • protein autoubiquitination • visual learning • regulation of behavioral fear response • chromatin organization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5896	19373
Ensembl	ENSG00000166349	ENSMUSG00000061311
UniProt	P15918	P15919
RefSeq (mRNA)	NM_000448	NM_009019
RefSeq (protein)	NP_000439 NP_001364206 NP_001364207 NP_001364208 NP_001364209	NP_033045
Location (UCSC)	Chr 11: 36.51 – 36.59 Mb	Chr 2: 101.64 – 101.65 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

The RAG1 and RAG2 genes are largely conserved in humans. 55.99% and 55.98% of the encoded amino acids contain no reported variants, respectively.[6]

Function

The protein encoded by this gene is involved in antibody and T-cell receptor V(D)J recombination. RAG-1 is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG-2. The RAG-1/2 complex recognizes recombination signal sequences (RSSs) that flank the V, D and J regions in the genes that encode the heavy and light chains of antibodies and components of T-cell receptors. The complex binds to the RSSs and nicks the DNA. This leads to the removal of the intervening DNA and the eventual ligation of the V, D and J sequences.[7] Defects in this gene can cause several different diseases.[5]

Clinical significance

Because of these effects, Rag1 deletion is used in mouse models of disease to impair T cell and B cell development, and functionally deletes mature T and B cells from the immune system.[8]

In humans, RAG deficiency was first recognised as a form of immune dysregulation known as Omenn syndrome. RAG deficiency is considered an autosomal recessive disease. The disorder is generally identified in infants. Complete loss-of-function in RAG1/2, the main components responsible for V(D)J recombination activity, produces severe immunodeficiency in humans. Hypomorphic RAG variants can retain partial recombination activity[9] and result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A).[10][11][12] RAG deficiency can be measured by in vitro quantification of recombination activity.[13][14][15] 71 RAG1 and 39 RAG2 variants have been functionally assayed to date (2019) (less than 10% of the potential point mutations that may cause disease). However, top candidate variants have been ranked by their predicted clinical relevance.[6]

References

1. GRCh38: Ensembl release 89: ENSG00000166349 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000061311 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Recombination activating gene 1".
6. Lawless D, Lango Allen H, Thaventhiran J, Hodel F, Anwar R, Fellay J, et al. (August 2019). "Predicting the Occurrence of Variants in RAG1 and RAG2". Journal of Clinical Immunology. 39 (7): 688–701. doi:10.1007/s10875-019-00670-z. PMC 6754361. PMID 31388879.
7. Owen J, Punt J, Stranford S, Jones P (2013). Kuby Immunology. New York: W. H. Freeman and Company. pp. 234–237. ISBN 978-14292-1919-8.
8. "B6.129S7-Rag1tm1Mom/J Mouse Strain Details". Jackson Laboratories.
9. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. (May 1998). "Partial V(D)J recombination activity leads to Omenn syndrome". Cell. 93 (5): 885–96. doi:10.1016/s0092-8674(00)81448-8. PMID 9630231. S2CID 1527777.
10. Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, et al. (May 2008). "An immunodeficiency disease with RAG mutations and granulomas". The New England Journal of Medicine. 358 (19): 2030–8. doi:10.1056/nejmoa073966. PMID 18463379.
11. Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. (November 2015). "Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency". The Journal of Clinical Investigation. 125 (11): 4135–48. doi:10.1172/jci80477. PMC 4639965. PMID 26457731.
12. Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. (August 2014). "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States". JAMA. 312 (7): 729–38. doi:10.1001/jama.2014.9132. PMC 4492158. PMID 25138334.
13. Lawless D, Geier CB, Farmer JR, Lango Allen H, Thwaites D, Atschekzei F, et al. (June 2018). "Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency". The Journal of Allergy and Clinical Immunology. 141 (6): 2303–2306. doi:10.1016/j.jaci.2018.02.007. PMC 6058308. PMID 29477728.
14. Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, et al. (April 2014). "A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency". The Journal of Allergy and Clinical Immunology. 133 (4): 1099–108. doi:10.1016/j.jaci.2013.10.007. PMC 4005599. PMID 24290284.
15. Tirosh I, Yamazaki Y, Frugoni F, Ververs FA, Allenspach EJ, Zhang Y, et al. (February 2019). "Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype". The Journal of Allergy and Clinical Immunology. 143 (2): 726–735. doi:10.1016/j.jaci.2018.04.027. PMC 6295349. PMID 29772310.