RAG1
Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene.[5]
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
[edit]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
[edit]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] as well as other milder forms, such as antibody deficiency,[13] Idiopathic CD4+ T lymphopenia [14] or vasculitis.[15] RAG deficiency can be measured by in vitro quantification of recombination activity.[16][17][18] 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
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000166349 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000061311 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: Recombination activating gene 1".
- ^ a b Lawless D, Lango Allen H, Thaventhiran J, Hodel F, Anwar R, Fellay J, et al. (October 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.
- ^ 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.
- ^ "B6.129S7-Rag1tm1Mom/J Mouse Strain Details". Jackson Laboratories.
- ^ 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): 885–896. doi:10.1016/s0092-8674(00)81448-8. PMID 9630231. S2CID 1527777.
- ^ 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): 2030–2038. doi:10.1056/nejmoa073966. PMID 18463379.
- ^ 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): 4135–4148. doi:10.1172/jci80477. PMC 4639965. PMID 26457731.
- ^ 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): 729–738. doi:10.1001/jama.2014.9132. PMC 4492158. PMID 25138334.
- ^ Geier CB, Piller A, Linder A, Sauerwein KM, Eibl MM, Wolf HM (2015-07-17). Rieux-Laucat F (ed.). "Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens". PLOS ONE. 10 (7): e0133220. Bibcode:2015PLoSO..1033220G. doi:10.1371/journal.pone.0133220. PMC 4506145. PMID 26186701.
- ^ Kuijpers TW, Ijspeert H, van Leeuwen EM, Jansen MH, Hazenberg MD, Weijer KC, et al. (June 2011). "Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations". Blood. 117 (22): 5892–5896. doi:10.1182/blood-2011-01-329052. PMID 21502542. S2CID 41743158.
- ^ Geier CB, Farmer JR, Foldvari Z, Ujhazi B, Steininger J, Sleasman JW, et al. (2020-10-21). "Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency". Frontiers in Immunology. 11: 574738. doi:10.3389/fimmu.2020.574738. PMC 7609967. PMID 33193364.
- ^ 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.
- ^ 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): 1099–1108. doi:10.1016/j.jaci.2013.10.007. PMC 4005599. PMID 24290284.
- ^ 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.
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