IRF6

IRF6
Identifikatori
Aliasi	IRF6
Vanjski ID-jevi	OMIM: 607199 MGI: 1859211 HomoloGene: 4479 GeneCards: IRF6
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	209,806,175 bp
Lokacija gena (miš)
Hrom.	Hromosom 1 (miš)
Kraj	192,854,331 bp
Ontologija gena
Molekularna funkcija	• vezivanje sa DNK; • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity; • GO:0001948, GO:0016582 vezivanje za proteine; • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific; • sequence-specific DNA binding; • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific;
Ćelijska komponenta	• citoplazma; • Egzosom; • jedro; • citosol; • međućelijske veze;
Biološki proces	• Ćelijska diferencijacija; • GO:0009373 regulation of transcription, DNA-templated; • cell development; • interferon-gamma-mediated signaling pathway; • transcription, DNA-templated; • mammary gland epithelial cell differentiation; • keratinocyte differentiation; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • keratinocyte proliferation; • type I interferon signaling pathway; • skin development; • negative regulation of cell population proliferation; • transcription by RNA polymerase II; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • immune system process; • roof of mouth development;
	Izvori:Amigo / QuickGO
Ortolozi
	3664
	54139
	ENSG00000117595
	ENSMUSG00000026638
	O14896
	P97431
	NM_006147; NM_001206696
	NM_016851; NM_178083
	NP_001193625; NP_006138
	NP_058547
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Interferonski regulatorni faktor 6, znan i kao IRF6, jest protein koji je kod ljudi kodiran genom IRF6 sa hromosoma 1..^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 467 aminokiselina, a molekulska težina 53.130 Da.^[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
MALHPRRVRL	KPWLVAQVDS	GLYPGLIWLH	RDSKRFQIPW	KHATRHSPQQ
EEENTIFKAW	AVETGKYQEG	VDDPDPAKWK	AQLRCALNKS	REFNLMYDGT
KEVPMNPVKI	YQVCDIPQPQ	GSIINPGSTG	SAPWDEKDND	VDEEDEEDEL
DQSQHHVPIQ	DTFPFLNING	SPMAPASVGN	CSVGNCSPEA	VWPKTEPLEM
EVPQAPIQPF	YSSPELWISS	LPMTDLDIKF	QYRGKEYGQT	MTVSNPQGCR
LFYGDLGPMP	DQEELFGPVS	LEQVKFPGPE	HITNEKQKLF	TSKLLDVMDR
GLILEVSGHA	IYAIRLCQCK	VYWSGPCAPS	LVAPNLIERQ	KKVKLFCLET
FLSDLIAHQK	GQIEKQPPFE	IYLCFGEEWP	DGKPLERKLI	LVQVIPVVAR
MIYEMFSGDF	TRSFDSGSVR	LQISTPDIKD	NIVAQLKQLY	RILQTQESWQ
PMQPTPSMQL	PPALPPQ

Funkcija

Ovaj gen kodira člana porodice interferonskih regulatornih transkripcijskih faktora (IRF). Članovi porodice dijele visoko konzerviran N-terminal helix-turn-helix DNK-vezujući domen i manje očuvan C-terminal domen za vezivanje proteina.^[7] Funkcija IRF6 povezana je s formiranjem veznog tkiva, na primjer onog nepca.^[8] Ovaj gen kodira člana porodice interferonskog regulatornog transkripcionog faktora (IRF). Osim toga, uočeno je da je gen IRF6 pod epigenetičkom regulacijom promotora metilacij DNK.^[9]

Patologija

Mutacija IRF6 gena može dovesti do autosomno dominantnog van der Woudeovog sindroma (VWS)^[10] ili srodnog sindroma poplitelnog pterigija (PPS).^[11] Van der Woudeov sindrom može uključivati rascjep usne i nepca, zajedno sa dentalnim anomalijama i fistulama usana. Osim toga, uobičajeni aleli u IRF6 su također povezani sa nesindromskim slučajevima rascjepa usne i/ili nepca prema studiji asocijacije na cijelom genomu i u mnogim studijama kandidata za gen.^[12] Ovi poremećaji uzrokovani su mutacijama u genu IRF6, a dio fenotipske heterogenosti uzrokovan je različitim tipovima mutacija IRF6-a.^[5] Jedno objašnjenje za ovu fenotipsku varijaciju između sindroma zasniva se na različitom uticaju na strukturu dimerizovanih mutantnih proteina. Čini se da VWS mutacije rezultiraju haploinsuficijencijom dok PPS mutacije mogu biti dominantno negativne prirode.^[13] Spektar mutacija u VWS i PPS nedavno je sumarizovan.^[14] Pokazalo se da IRF6 ima ključnu ulogu u razvoju keratinocita.^[15]^[16] Uloga IRF6 u uobičajenim oblicima je također demonstrirana je i u slučajevima rascjepa usne i nepca ^[17] i može objasniti samo ~20% slučajeva rascjepa usne.^[18] Varijante u IRF6 dale su dosljedne dokaze o povezanosti sa sindromskim rascjepom i/ili nepcem u više studija. Studija Birnbauma i kolega iz 2009. godine potvrdila je uticaj ovog gena na etiologiju rascjepa usne i/ili nepca, a studija GENEVA Cleft Consortium, koja je proučavala porodice iz više populacija, ponovo je potvrdila nalaze da su mutacije IRF6 snažno povezane s rascjepom usne i/ili nepca. Uloga IRF6 u izazivanju rascjepa usne i/ili nepca dalje je podržana analizom IRF6 mutantnih miševa koji pokazuju hiperproliferativnu epidermu koja ne prolazi kroz terminalnu diferencijaciju, što dovodi do višestrukih epitelnih adhezija koje mogu začepiti usnu šupljinu i rezultirati rascjepom nepca. Istraživanja na životinjskim modelima pokazuju da IRF6 određuje proliferaciju keratinocita i također ima ključnu ulogu u formiranju usnn periderme. Nedavno, korištenjem genetike miša, analiza ekspresije gena, studija imunoprecipitacije hromatina i testova reportera luciferaze, pokazalo se da je IRF6 direktna meta p63, koji je u osnovi nekoliko sindromskih malformacija, koje uključuju obilježja rascjepa, a p63 aktivira transkripciju IRF6 putem IRF6 pojačivačkog elementa. Varijacije u elementu pojačivača povećavaju podložnost samo rascjepu usne. I rascjep usne sa ili bez rascjepa nepca i samo rascjepom nepca uočene su u porodicama sa mutacijom IRF6-a. Osim toga, različiti tipovi rascjepa mogu se odvojiti unutar iste porodice.^[12]

Epigenetika

Uočeno je da je aberantni promotor IRF6 hipermetilacije DNK povezan sa pojavom/progresijom raka. Zaista, ovaj neprikladan epigenetički fenomen uočen je kod žena zahvaćenih kancerom vulvinih pločastih ćelija nastao je iz vulver lichen sclerosus.^[19] Metilacija promotora IRF6 može biti marker rizika od raka kod pacijenata oboljelih od ove bolesti.^[9]

Kancer

Uočeno je da je gen IRF6 progresivno smanjen u ljudski papiloma virus-pozitivnim neoplastični keratinociti izvedenim iz cerviksne preneoplazijske lezije na različitim nivoima malignosti.^[20] Iz tog razloga, ovaj gen je vjerovatno povezan s tumorigenezom i može biti potencijalni prognostički marker za progresiju preneoplazijske lezije grlića maternice.^[20] Slično tome, otkriveno je da je IRF6 genetički i epigenetički nereguliran u raku vulve.^[9]

Također pogledajte

Interferonski regulatorni faktori

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000117595 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000026638 - 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 Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC (oktobar 2002). "Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes". Nat. Genet. 32 (2): 285–9. doi:10.1038/ng985. PMC 3169431. PMID 12219090.
^ "UniProt, O14896" (jezik: engleski). Pristupljeno 13. 12. 2021.
^ "Entrez Gene: IRF6".
^ Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT (septembar 2005). "Variation in IRF6 contributes to nonsyndromic cleft lip and palate". Am. J. Med. Genet. A. 137A (3): 259–62. doi:10.1002/ajmg.a.30887. PMID 16096995. S2CID 25084563.
^ ^a ^b ^c Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, Corazza M, Virgili A, Tognon M, Martini F (2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.
^ Van der Woude, A (juni 1954). "Fistula labii inferioris congenita and its association with cleft lip and palate". Am. J. Hum. Genet. 6 (2): 244–56. PMC 1716548. PMID 13158329.
^ Gorlin RJ, Sedano HO, Cervenka J (februar 1968). "Popliteal pterygium syndrome . A syndrome comprising cleft lip-palate, popliteal and intercrural pterygia, digital and genital anomalies". Pediatrics. 41 (2): 503–9. PMID 4384166.
^ ^a ^b Dixon MJ, Marazita ML, Beaty TH, Murray JC (mart 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nat. Rev. Genet. 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.
^ Little HJ, Rorick NK, Su LI, Baldock C, Malhotra S, Jowitt T, Gakhar L, Subramanian R, Schutte BC, Dixon MJ, Shore P (novembar 2008). "Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6". Hum. Mol. Genet. 18 (3): 535–45. doi:10.1093/hmg/ddn381. PMC 2638798. PMID 19036739.
^ de Lima RL, Hoper SA, Ghassibe M, et al. (april 2009). "Prevalence and non-random distribution of exonic mutations in Interferon Regulatory Factor 6 (IRF6) in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome". Genet. Med. 11 (4): 241–7. doi:10.1097/GIM.0b013e318197a49a. PMC 2789395. PMID 19282774.
^ Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, Shore P, Whitmarsh A, Dixon MJ (novembar 2006). "Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch". Nat. Genet. 38 (11): 1329–34. doi:10.1038/ng1894. PMID 17041603. S2CID 13102953.
^ Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M, Murray JC, Schutte BC (novembar 2006). "Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6)". Nat. Genet. 38 (11): 1335–40. doi:10.1038/ng1903. PMC 2082114. PMID 17041601.
^ Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC (august 2004). "Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate". N. Engl. J. Med. 351 (8): 769–80. doi:10.1056/NEJMoa032909. PMID 15317890.
^ Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ, Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, Murray JC (novembar 2008). "Disruption of an AP-2α binding site in an IRF6 enhancer is strongly associated with cleft lip". Nat. Genet. 40 (11): 1341–7. doi:10.1038/ng.242. PMC 2691688. PMID 18836445.
^ Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, Corazza M, Virgili A, Tognon M, Martini F (2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.
^ ^a ^b Rotondo JC, Bosi S, Bassi C, Ferracin M, Lanza G, Gafà R, Magri E, Selvatici R, Torresani S, Marci R, Garutti P, Negrini M, Tognon M, Martini F (april 2015). "Gene expression changes in progression of cervical neoplasia revealed by microarray analysis of cervical neoplastic keratinocytes". J Cell Physiol. 230 (4): 802–812. doi:10.1002/jcp.24808. PMID 25205602. S2CID 24986454.

Vanjski linkovi

GeneReview/NIH/UW entry on IRF6-Related Disorders
IRF6 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
IRF6 lokacija ljudskog genoma UCSC Genome Browser.

IRF6 detalji ljudskog genoma u UCSC Genome Browser.

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000117595 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000026638 - 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.

[pmid12219090-5] Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC (oktobar 2002). "Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes". Nat. Genet. 32 (2): 285–9. doi:10.1038/ng985. PMC 3169431. PMID 12219090.

[UniProt-6] "UniProt, O14896" (jezik: engleski). Pristupljeno 13. 12. 2021.

[entrez-7] "Entrez Gene: IRF6".

[pmid16096995-8] Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT (septembar 2005). "Variation in IRF6 contributes to nonsyndromic cleft lip and palate". Am. J. Med. Genet. A. 137A (3): 259–62. doi:10.1002/ajmg.a.30887. PMID 16096995. S2CID 25084563.

[pmid27223861-9] Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, Corazza M, Virgili A, Tognon M, Martini F (2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.

[pmid13158329-10] Van der Woude, A (juni 1954). "Fistula labii inferioris congenita and its association with cleft lip and palate". Am. J. Hum. Genet. 6 (2): 244–56. PMC 1716548. PMID 13158329.

[pmid4384166-11] Gorlin RJ, Sedano HO, Cervenka J (februar 1968). "Popliteal pterygium syndrome . A syndrome comprising cleft lip-palate, popliteal and intercrural pterygia, digital and genital anomalies". Pediatrics. 41 (2): 503–9. PMID 4384166.

[pmid21331089-12] Dixon MJ, Marazita ML, Beaty TH, Murray JC (mart 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nat. Rev. Genet. 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.

[pmid19036739-13] Little HJ, Rorick NK, Su LI, Baldock C, Malhotra S, Jowitt T, Gakhar L, Subramanian R, Schutte BC, Dixon MJ, Shore P (novembar 2008). "Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6". Hum. Mol. Genet. 18 (3): 535–45. doi:10.1093/hmg/ddn381. PMC 2638798. PMID 19036739.

[pmid19282774-14] Lima RL, Hoper SA, Ghassibe M, et al. (april 2009). "Prevalence and non-random distribution of exonic mutations in Interferon Regulatory Factor 6 (IRF6) in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome". Genet. Med. 11 (4): 241–7. doi:10.1097/GIM.0b013e318197a49a. PMC 2789395. PMID 19282774.

[pmid17041603-15] Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, Shore P, Whitmarsh A, Dixon MJ (novembar 2006). "Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch". Nat. Genet. 38 (11): 1329–34. doi:10.1038/ng1894. PMID 17041603. S2CID 13102953.

[pmid17041601-16] Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M, Murray JC, Schutte BC (novembar 2006). "Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6)". Nat. Genet. 38 (11): 1335–40. doi:10.1038/ng1903. PMC 2082114. PMID 17041601.

[pmid15317890-17] Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC (august 2004). "Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate". N. Engl. J. Med. 351 (8): 769–80. doi:10.1056/NEJMoa032909. PMID 15317890.

[pmid18836445-18] Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ, Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, Murray JC (novembar 2008). "Disruption of an AP-2α binding site in an IRF6 enhancer is strongly associated with cleft lip". Nat. Genet. 40 (11): 1341–7. doi:10.1038/ng.242. PMC 2691688. PMID 18836445.

[Rotondo_201-19] Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, Corazza M, Virgili A, Tognon M, Martini F (2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.

[Rotondo_2015-20] Rotondo JC, Bosi S, Bassi C, Ferracin M, Lanza G, Gafà R, Magri E, Selvatici R, Torresani S, Marci R, Garutti P, Negrini M, Tognon M, Martini F (april 2015). "Gene expression changes in progression of cervical neoplasia revealed by microarray analysis of cervical neoplastic keratinocytes". J Cell Physiol. 230 (4): 802–812. doi:10.1002/jcp.24808. PMID 25205602. S2CID 24986454.

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