RAG1

RAG1
Identifikatori
Aliasi	RAG1
Vanjski ID-jevi	OMIM: 179615 MGI: 97848 HomoloGene: 387 GeneCards: RAG1
Lokacija gena (čovjek)
Hrom.	Hromosom 11 (čovjek)
Kraj	36,593,156 bp
Lokacija gena (miš)
Hrom.	Hromosom 2 (miš)
Kraj	101,479,846 bp
Ontologija gena
Molekularna funkcija	• vezivanje sa DNK; • sequence-specific DNA binding; • protein homodimerization activity; • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity; • GO:0031493 histone binding; • vezivanje iona cinka; • vezivanje iona metala; • GO:0050372 aktivnost sa transferazom ubikvitina; • GO:0001948, GO:0016582 vezivanje za proteine; • catalytic activity; • nuclease activity; • endonuclease activity; • hydrolase activity; • aktivnost sa transferazom; • vezivanje identičnih proteina; • double-stranded DNA endodeoxyribonuclease activity;
Ćelijska komponenta	• nukleoplazma; • jedro; • DNA recombinase complex; • endodeoxyribonuclease complex;
Biološki proces	• 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; • GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor; • V(D)J rekombinacija; • pre-B cell allelic exclusion; • B cell differentiation; • metabolizam; • regulation of T cell differentiation; • protein autoubiquitination; • visual learning; • regulation of behavioral fear response; • GO:0031497, GO:0006336, GO:0034724, GO:0001301, GO:0007580, GO:0034652, GO:0010847 chromatin organization;
	Izvori:Amigo / QuickGO
Ortolozi
	5896
	19373
	ENSG00000166349
	ENSMUSG00000061311
	P15918
	P15919
	NM_000448
	NM_009019
	NP_000439; NP_001364206; NP_001364207; NP_001364208; NP_001364209
	NP_033045
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Recombinacijsko
aktivacijki gen 1 znan i kao RAG-1 je protein koji je kod ljudi kodiran genom RAG1.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 1.043 aminokiseline, a molekulska težina 119 097Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MAASFPPTLG	LSSAPDEIQH	PHIKFSEWKF	KLFRVRSFEK	TPEEAQKEKK
DSFEGKPSLE	QSPAVLDKAD	GQKPVPTQPL	LKAHPKFSKK	FHDNEKARGK
AIHQANLRHL	CRICGNSFRA	DEHNRRYPVH	GPVDGKTLGL	LRKKEKRATS
WPDLIAKVFR	IDVKADVDSI	HPTEFCHNCW	SIMHRKFSSA	PCEVYFPRNV
TMEWHPHTPS	CDICNTARRG	LKRKSLQPNL	QLSKKLKTVL	DQARQARQHK
RRAQARISSK	DVMKKIANCS	KIHLSTKLLA	VDFPEHFVKS	ISCQICEHIL
ADPVETNCKH	VFCRVCILRC	LKVMGSYCPS	CRYPCFPTDL	ESPVKSFLSV
LNSLMVKCPA	KECNEEVSLE	KYNHHISSHK	ESKEIFVHIN	KGGRPRQHLL
SLTRRAQKHR	LRELKLQVKA	FADKEEGGDV	KSVCMTLFLL	ALRARNEHRQ
ADELEAIMQG	KGSGLQPAVC	LAIRVNTFLS	CSQYHKMYRT	VKAITGRQIF
QPLHALRNAE	KVLLPGYHHF	EWQPPLKNVS	SSTDVGIIDG	LSGLSSSVDD
YPVDTIAKRF	RYDSALVSAL	MDMEEDILEG	MRSQDLDDYL	NGPFTVVVKE
SCDGMGDVSE	KHGSGPVVPE	KAVRFSFTIM	KITIAHSSQN	VKVFEEAKPN
SELCCKPLCL	MLADESDHET	LTAILSPLIA	EREAMKSSEL	MLELGGILRT
FKFIFRGTGY	DEKLVREVEG	LEASGSVYIC	TLCDATRLEA	SQNLVFHSIT
RSHAENLERY	EVWRSNPYHE	SVEELRDRVK	GVSAKPFIET	VPSIDALHCD
IGNAAEFYKI	FQLEIGEVYK	NPNASKEERK	RWQATLDKHL	RKKMNLKPIM
RMNGNFARKL	MTKETVDAVC	ELIPSEERHE	ALRELMDLYL	KMKPVWRSSC
PAKECPESLC	QYSFNSQRFA	ELLSTKFKYR	YEGKITNYFH	KTLAHVPEII
ERDGSIGAWA	SEGNESGNKL	FRRFRKMNAR	QSKCYEMEDV	LKHHWLYTSK
YLQKFMNAHN	ALKTSGFTMN	PQASLGDPLG	IEDSLESQDS	MEF

Funkcija

Geni RAG1 i RAG2 uglavnom su konzervirani kod ljudi. 55,99% i 55,98% kodiranih aminokiselina ne sadrže prijavljene varijante. Protei n kodiran ovim genom uključen je u antitijela i T-ćelijski receptor V (D) J rekombinacija. RAG-1 je uključen u prepoznavanje DNK supstrata, ali stabilna aktivnost vezivanja i cijepanja također zahtijeva RAG2. RAG-1/2 kompleks prepoznaje rekombinacijske signalne sekvence (RSS-ove) koji okružuju V, D i J regije u genima koji kodiraju teški i lahki lanci antitijela i komponenti receptora T-ćelija. Kompleks se veže za RSS ove i probija DNK. To dovodi do uklanjanja intervenirajuće DNK i konačne ligacije V, D i J sekvenci.^[7] Defekti ovog gena mogu uzrokovati nekoliko različitih bolesti.^[5]

Klinički značaj

Zbog ovih učinaka, delecija Rag1 koristi se u mišjim modelima bolesti za narušavanje razvoja T– i B-ćelija, te funkcionalno deletira zrele T i B ćelije iz imunkog ssistema.^[8]

Kod ljudi, nedostatak RAG-a prvi put prepoznat je kao oblik imunske disregulacije, poznat kao Omennov sindrom. Nedostatak RAG-a smatra se autosomno recesivnom bolešću. Poremećaj se općenito identificira kod dojenčadi. Potpuni gubitak funkcije u RAG1/2, glavne komponente odgovorne za rekombinacijsku aktivnost V (D) J, proizvodi ozbiljnu imunodeficijenciju kod ljudi. Hipomorfne varijante RAG-a mogu zadržati djelimičnu rekombinacijsku aktivnost^[9] i rezultira izrazitim fenotipom kombinovane imunodeficijencije sa granulomom i/ili autoimunitetom (CID-G/A).^[10]^[11]^[12] Nedostatak RAG-a može se mjeriti in vitro kvantifikacijom rekombinacijske aktivnosti.^[13]^[14]^[15] Do danas je funkcionalno ispitano 71 varijanta RAG1 i 39 RAG2 (manje od 10% potencijalnih tačkastih mutacija koje mogu uzrokovati bolest). Međutim, varijante najboljih kandidata rangirane su prema njihovoj predviđenoj kliničkoj važnosti.^[16]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000166349 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000061311 - Ensembl, maj 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".
^ "UniProt, P15918". Pristupljeno 25. 8. 2021.
^ Owen J, Punt J, Stranford S, Jones P (2013). Kuby Immunology. New York: W. H. Freeman and Company. str. 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. (maj 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.
^ Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, et al. (maj 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.
^ Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. (novembar 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.
^ 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.
^ Lawless D, Geier CB, Farmer JR, Lango Allen H, Thwaites D, Atschekzei F, et al. (juni 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): 1099–108. 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. (februar 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.
^ 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.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000166349 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000061311 - Ensembl, maj 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.

[entrez-5] "Entrez Gene: Recombination activating gene 1".

[UniProt-6] "UniProt, P15918". Pristupljeno 25. 8. 2021.

[7] Owen J, Punt J, Stranford S, Jones P (2013). Kuby Immunology. New York: W. H. Freeman and Company. str. 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. (maj 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. (maj 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. (novembar 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. (juni 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. (februar 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.

[:0-16] 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.

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