RAG1 - Wikipedia

Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene. The RAG1 and RAG2 genes are largely conserved ... RAG1 FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch RAG1IdentifiersAliasesRAG1,RAG-1,RNF74,recombinationactivatinggene1,recombinationactivating1ExternalIDsOMIM:179615MGI:97848HomoloGene:387GeneCards:RAG1Genelocation(Human)Chr.Chromosome11(human)[1]Band11p12Start36,510,709bp[1]End36,593,156bp[1]Genelocation(Mouse)Chr.Chromosome2(mouse)[2]Band2E2|253.88cMStart101,468,627bp[2]End101,479,846bp[2]RNAexpressionpatternBgeeTopexpressedin thymus bonemarrow suralnerve thyroidgland testicle ovary spleen colonMorereferenceexpressiondataBioGPSn/aGeneontologyMolecularfunction DNAbinding sequence-specificDNAbinding proteinhomodimerizationactivity GO:1904264,GO:1904822,GO:0090622,GO:0090302ubiquitinproteinligaseactivity histonebinding zincionbinding metalionbinding ubiquitin-proteintransferaseactivity GO:0001948proteinbinding catalyticactivity nucleaseactivity endonucleaseactivity hydrolaseactivity transferaseactivity identicalproteinbinding double-strandedDNAendodeoxyribonucleaseactivity Cellularcomponent nucleoplasm nucleus DNArecombinasecomplex endodeoxyribonucleasecomplex Biologicalprocess positiveregulationofTcelldifferentiation histonemonoubiquitination DNArecombination negativeregulationofcysteine-typeendopeptidaseactivityinvolvedinapoptoticprocess adaptiveimmuneresponse Tcelldifferentiationinthymus nucleicacidphosphodiesterbondhydrolysis thymusdevelopment negativeregulationofthymocyteapoptoticprocess Tcellhomeostasis negativeregulationofTcellapoptoticprocess immuneresponse V(D)Jrecombination pre-Bcellallelicexclusion Bcelldifferentiation metabolism regulationofTcelldifferentiation proteinautoubiquitination visuallearning regulationofbehavioralfearresponse chromatinorganization Sources:Amigo/QuickGOOrthologsSpeciesHumanMouseEntrez589619373EnsemblENSG00000166349ENSMUSG00000061311UniProtP15918P15919RefSeq(mRNA)NM_000448NM_009019RefSeq(protein)NP_000439NP_001364206NP_001364207NP_001364208NP_001364209NP_033045Location(UCSC)Chr11:36.51–36.59MbChr2:101.47–101.48MbPubMedsearch[3][4]WikidataView/EditHumanView/EditMouse Recombinationactivatinggene1alsoknownasRAG-1isaproteinthatinhumansisencodedbytheRAG1gene.[5] TheRAG1andRAG2genesarelargelyconservedinhumans.55.99%and55.98%oftheencodedaminoacidscontainnoreportedvariants,respectively.[6] Function[edit] TheproteinencodedbythisgeneisinvolvedinantibodyandT-cellreceptorV(D)Jrecombination.RAG-1isinvolvedinrecognitionoftheDNAsubstrate,butstablebindingandcleavageactivityalsorequiresRAG-2.TheRAG-1/2complexrecognizesrecombinationsignalsequences(RSSs)thatflanktheV,DandJregionsinthegenesthatencodetheheavyandlightchainsofantibodiesandcomponentsofT-cellreceptors.ThecomplexbindstotheRSSsandnickstheDNA.ThisleadstotheremovaloftheinterveningDNAandtheeventualligationoftheV,DandJsequences.[7]Defectsinthisgenecancauseseveraldifferentdiseases.[5] Clinicalsignificance[edit] Becauseoftheseeffects,Rag1deletionisusedinmousemodelsofdiseasetoimpairTcellandBcelldevelopment,andfunctionallydeletesmatureTandBcellsfromtheimmunesystem.[8] Inhumans,RAGdeficiencywasfirstrecognisedasaformofimmunedysregulationknownasOmennsyndrome.RAGdeficiencyisconsideredanautosomalrecessivedisease.Thedisorderisgenerallyidentifiedininfants.Completeloss-of-functioninRAG1/2,themaincomponentsresponsibleforV(D)Jrecombinationactivity,producessevereimmunodeficiencyinhumans.HypomorphicRAGvariantscanretainpartialrecombinationactivity[9]andresultinadistinctphenotypeofcombinedimmunodeficiencywithgranulomaand/orautoimmunity(CID-G/A),[10][11][12]aswellasothermilderforms,suchasantibodydeficiency,[13]IdiopathicCD4+Tlymphopenia[14]orvasculitis.[15]RAGdeficiencycanbemeasuredbyinvitroquantificationofrecombinationactivity.[16][17][18]71RAG1and39RAG2variantshavebeenfunctionallyassayedtodate(2019)(lessthan10%ofthepotentialpointmutationsthatmaycausedisease).However,topcandidatevariantshavebeenrankedbytheirpredictedclinicalrelevance.[6] References[edit] ^abcGRCh38:Ensemblrelease89:ENSG00000166349-Ensembl,May2017 ^abcGRCm38:Ensemblrelease89:ENSMUSG00000061311-Ensembl,May2017 ^"HumanPubMedReference:".NationalCenterforBiotechnologyInformation,U.S.NationalLibraryofMedicine. ^"MousePubMedReference:".NationalCenterforBiotechnologyInformation,U.S.NationalLibraryofMedicine. ^ab"EntrezGene:Recombinationactivatinggene1". ^abLawlessD,LangoAllenH,ThaventhiranJ,HodelF,AnwarR,FellayJ,et al.(October2019)."PredictingtheOccurrenceofVariantsinRAG1andRAG2".JournalofClinicalImmunology.39(7):688–701.doi:10.1007/s10875-019-00670-z.PMC 6754361.PMID 31388879. ^OwenJ,PuntJ,StranfordS,JonesP(2013).KubyImmunology.NewYork:W.H.FreemanandCompany.pp. 234–237.ISBN 978-14292-1919-8. ^"B6.129S7-Rag1tm1Mom/JMouseStrainDetails".JacksonLaboratories. ^VillaA,SantagataS,BozziF,GilianiS,FrattiniA,ImbertiL,et al.(May1998)."PartialV(D)JrecombinationactivityleadstoOmennsyndrome".Cell.93(5):885–896.doi:10.1016/s0092-8674(00)81448-8.PMID 9630231.S2CID 1527777. ^SchuetzC,HuckK,GudowiusS,MegahedM,FeyenO,HubnerB,et al.(May2008)."AnimmunodeficiencydiseasewithRAGmutationsandgranulomas".TheNewEnglandJournalofMedicine.358(19):2030–2038.doi:10.1056/nejmoa073966.PMID 18463379. ^WalterJE,RosenLB,CsomosK,RosenbergJM,MathewD,KeszeiM,et al.(November2015)."Broad-spectrumantibodiesagainstself-antigensandcytokinesinRAGdeficiency".TheJournalofClinicalInvestigation.125(11):4135–4148.doi:10.1172/jci80477.PMC 4639965.PMID 26457731. ^KwanA,AbrahamRS,CurrierR,BrowerA,AndruszewskiK,AbbottJK,et al.(August2014)."Newbornscreeningforseverecombinedimmunodeficiencyin11screeningprogramsintheUnitedStates".JAMA.312(7):729–738.doi:10.1001/jama.2014.9132.PMC 4492158.PMID 25138334. ^GeierCB,PillerA,LinderA,SauerweinKM,EiblMM,WolfHM(2015-07-17).Rieux-LaucatF(ed.)."LeakyRAGDeficiencyinAdultPatientswithImpairedAntibodyProductionagainstBacterialPolysaccharideAntigens".PLOSONE.10(7):e0133220.Bibcode:2015PLoSO..1033220G.doi:10.1371/journal.pone.0133220.PMC 4506145.PMID 26186701. ^KuijpersTW,IjspeertH,vanLeeuwenEM,JansenMH,HazenbergMD,WeijerKC,et al.(June2011)."IdiopathicCD4+TlymphopeniawithoutautoimmunityorgranulomatousdiseaseintheslipstreamofRAGmutations".Blood.117(22):5892–5896.doi:10.1182/blood-2011-01-329052.PMID 21502542. ^GeierCB,FarmerJR,FoldvariZ,UjhaziB,SteiningerJ,SleasmanJW,et al.(2020-10-21)."VasculitisasaMajorMorbidityFactorinPatientsWithPartialRAGDeficiency".FrontiersinImmunology.11:574738.doi:10.3389/fimmu.2020.574738.PMC 7609967.PMID 33193364. ^LawlessD,GeierCB,FarmerJR,LangoAllenH,ThwaitesD,AtschekzeiF,et al.(June2018)."Prevalenceandclinicalchallengesamongadultswithprimaryimmunodeficiencyandrecombination-activatinggenedeficiency".TheJournalofAllergyandClinicalImmunology.141(6):2303–2306.doi:10.1016/j.jaci.2018.02.007.PMC 6058308.PMID 29477728. ^LeeYN,FrugoniF,DobbsK,WalterJE,GilianiS,GenneryAR,et al.(April2014)."Asystematicanalysisofrecombinationactivityandgenotype-phenotypecorrelationinhumanrecombination-activatinggene1deficiency".TheJournalofAllergyandClinicalImmunology.133(4):1099–1108.doi:10.1016/j.jaci.2013.10.007.PMC 4005599.PMID 24290284. ^TiroshI,YamazakiY,FrugoniF,VerversFA,AllenspachEJ,ZhangY,et al.(February2019)."Recombinationactivityofhumanrecombination-activatinggene2(RAG2)mutationsandcorrelationwithclinicalphenotype".TheJournalofAllergyandClinicalImmunology.143(2):726–735.doi:10.1016/j.jaci.2018.04.027.PMC 6295349.PMID 29772310. 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