RAG1 explained

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

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.

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.[2] Defects in this gene can cause several different diseases.[1]

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.[3]

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[4] and result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A),[5] [6] [7] as well as other milder forms, such as antibody deficiency,[8] Idiopathic CD4+ T lymphopenia [9] or vasculitis.[10] RAG deficiency can be measured by in vitro quantification of recombination activity.[11] [12] [13] 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.[14]

Notes and References

  1. Web site: Entrez Gene: Recombination activating gene 1 .
  2. Book: Kuby Immunology . Owen . Judy . Punt . Jenni . Stranford . Sharon . Jones . Patricia . vanc . W. H. Freeman and Company . 2013 . 978-14292-1919-8 . New York . 234–237 .
  3. Web site: B6.129S7-Rag1tm1Mom/J Mouse Strain Details. Jackson Laboratories.
  4. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, Gatta LB, Ochs HD, Schwarz K, Notarangelo LD, Vezzoni P, Spanopoulou E . 6 . Partial V(D)J recombination activity leads to Omenn syndrome . Cell . 93 . 5 . 885–896 . May 1998 . 9630231 . 10.1016/s0092-8674(00)81448-8 . 1527777 . free .
  5. Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, Knüchel R, Göbel U, Schulz A, Borkhardt A, Friedrich W, Schwarz K, Niehues T . 6 . An immunodeficiency disease with RAG mutations and granulomas . The New England Journal of Medicine . 358 . 19 . 2030–2038 . May 2008 . 18463379 . 10.1056/nejmoa073966 . free .
  6. Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD . 6 . Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency . The Journal of Clinical Investigation . 125 . 11 . 4135–4148 . November 2015 . 26457731 . 4639965 . 10.1172/jci80477 .
  7. Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, Baker M, Ballow M, Bartoshesky LE, Bonilla FA, Brokopp C, Brooks E, Caggana M, Celestin J, Church JA, Comeau AM, Connelly JA, Cowan MJ, Cunningham-Rundles C, Dasu T, Dave N, De La Morena MT, Duffner U, Fong CT, Forbes L, Freedenberg D, Gelfand EW, Hale JE, Hanson IC, Hay BN, Hu D, Infante A, Johnson D, Kapoor N, Kay DM, Kohn DB, Lee R, Lehman H, Lin Z, Lorey F, Abdel-Mageed A, Manning A, McGhee S, Moore TB, Naides SJ, Notarangelo LD, Orange JS, Pai SY, Porteus M, Rodriguez R, Romberg N, Routes J, Ruehle M, Rubenstein A, Saavedra-Matiz CA, Scott G, Scott PM, Secord E, Seroogy C, Shearer WT, Siegel S, Silvers SK, Stiehm ER, Sugerman RW, Sullivan JL, Tanksley S, Tierce ML, Verbsky J, Vogel B, Walker R, Walkovich K, Walter JE, Wasserman RL, Watson MS, Weinberg GA, Weiner LB, Wood H, Yates AB, Puck JM, Bonagura VR . 6 . Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States . JAMA . 312 . 7 . 729–738 . August 2014 . 25138334 . 4492158 . 10.1001/jama.2014.9132 .
  8. Geier CB, Piller A, Linder A, Sauerwein KM, Eibl MM, Wolf HM . Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens . PLOS ONE . 10 . 7 . e0133220 . 2015-07-17 . 26186701 . 4506145 . 10.1371/journal.pone.0133220 . Frederic . 2015PLoSO..1033220G . free . Rieux-Laucat .
  9. Kuijpers TW, Ijspeert H, van Leeuwen EM, Jansen MH, Hazenberg MD, Weijer KC, van Lier RA, van der Burg M . 6 . Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations . Blood . 117 . 22 . 5892–5896 . June 2011 . 21502542 . 10.1182/blood-2011-01-329052 . 41743158 . free .
  10. Geier CB, Farmer JR, Foldvari Z, Ujhazi B, Steininger J, Sleasman JW, Parikh S, Dilley MA, Pai SY, Henderson L, Hazen M, Neven B, Moshous D, Sharapova SO, Mihailova S, Yankova P, Naumova E, Özen S, Byram K, Fernandez J, Wolf HM, Eibl MM, Notarangelo LD, Calabrese LH, Walter JE . 6 . Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency . Frontiers in Immunology . 11 . 574738 . 2020-10-21 . 33193364 . 7609967 . 10.3389/fimmu.2020.574738 . free .
  11. Lawless D, Geier CB, Farmer JR, Lango Allen H, Thwaites D, Atschekzei F, Brown M, Buchbinder D, Burns SO, Butte MJ, Csomos K, Deevi SV, Egner W, Ehl S, Eibl MM, Fadugba O, Foldvari Z, Green DM, Henrickson SE, Holland SM, John T, Klemann C, Kuijpers TW, Moreira F, Piller A, Rayner-Matthews P, Romberg ND, Sargur R, Schmidt RE, Schröder C, Schuetz C, Sharapova SO, Smith KG, Sogkas G, Speckmann C, Stirrups K, Thrasher AJ, Wolf HM, Notarangelo LD, Anwar R, Boyes J, Ujhazi B, Thaventhiran J, Walter JE, Savic S . 6 . 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 . June 2018 . 29477728 . 6058308 . 10.1016/j.jaci.2018.02.007 .
  12. Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, Notarangelo LD . 6 . 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 . April 2014 . 24290284 . 4005599 . 10.1016/j.jaci.2013.10.007 .
  13. Tirosh I, Yamazaki Y, Frugoni F, Ververs FA, Allenspach EJ, Zhang Y, Burns S, Al-Herz W, Noroski L, Walter JE, Gennery AR, van der Burg M, Notarangelo LD, Lee YN . 6 . 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 . February 2019 . 29772310 . 6295349 . 10.1016/j.jaci.2018.04.027 .
  14. Lawless D, Lango Allen H, Thaventhiran J, Hodel F, Anwar R, Fellay J, Walter JE, Savic S . 6 . Predicting the Occurrence of Variants in RAG1 and RAG2 . Journal of Clinical Immunology . 39 . 7 . 688–701 . October 2019 . 31388879 . 6754361 . 10.1007/s10875-019-00670-z . free .

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