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IRF6

From Wikipedia, the free encyclopedia
Not to be confused with IrF6,the chemical formula forIridium hexafluoride.
IRF6
Identifiers
AliasesIRF6,LPS, OFC6, PIT, PPS, PPS1, VWS, VWS1, interferon regulatory factor 6
External IDsOMIM:607199;MGI:1859211;HomoloGene:4479;GeneCards:IRF6;OMA:IRF6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3664

54139

Ensembl

ENSG00000117595

ENSMUSG00000026638

UniProt

O14896

P97431

RefSeq (mRNA)

NM_006147
NM_001206696

NM_016851
NM_178083

RefSeq (protein)

NP_001193625
NP_006138

NP_058547

Location (UCSC)Chr 1: 209.79 – 209.81 MbChr 1: 192.84 – 192.85 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Interferon regulatory factor 6also known asIRF6is aproteinthat in humans is encoded by theIRF6gene.[5]

Function[edit]

This gene encodes a member of theinterferon regulatory transcription factor(IRF) family. Family members share a highly conservedN-terminalhelix-turn-helixDNA-binding domain and a less conservedC-terminalprotein-binding domain.[6]The function of IRF6 is related to the formation ofconnective tissue,for example that of thepalate.[7]This gene encodes a member of theinterferonregulatory transcription factor (IRF) family. In addition, it has been observed that IRF6 gene is under epigenetic regulation by promotermethylation.[8]

Pathology[edit]

Amutationof the IRF6genecan lead to the autosomal dominantvan der Woude syndrome(VWS)[9]or the relatedpopliteal pterygium syndrome(PPS).[10]Van der Woude syndrome can includecleft lip and palatefeatures along with dental anomalies and lip fistulas. In addition, common alleles in IRF6 have also been associated with non-syndromic cases of cleft lip and/or palate through genome-wide association studies and in many candidate gene studies.[11]These disorders are caused by mutations in the IRF6 gene and some of the phenotypic heterogeneity is due to different types of IRF6 mutations.[5] One explanation for this phenotypic variation between syndromes is based on a differential impact on the structure of the dimerized mutant proteins. VWS mutations appear to result inhaploinsufficiencywhile PPS mutations may bedominant negativein nature.[12]The spectrum of mutations in VWS and PPS has been recently summarized.[13]IRF6 has been shown to play a critical role in keratinocyte development.[14][15]A role for IRF6 in the common forms ofcleft lip and palatehas also been demonstrated[16]and may explain ~20% of cases of cleft lip only.[17]Variants in IRF6 have yielded consistent evidence of association with syndromic cleft and/or palate across multiple studies. A study by Birnbaum and colleagues in 2009 confirmed the impact of this gene on the etiology of cleft lip and/or palate, and the GENEVA Cleft Consortium study, which studied families from multiple populations, reconfirmed the findings that IRF6 mutations are strongly associated with cleft and/or palate. A role of IRF6 in causing cleft lip and/or palate is further supported by analysis of IRF6 mutant mice which exhibit a hyper-proliferative epidermis that fails to undergo terminal differentiation, leading to multiple epithelial adhesions that can occlude the oral cavity and result in cleft palate. Research on animal models indicate IRF6 determines keratinocyte proliferation and also has a key role in the formation of oral periderm. Recently, through utilization of mouse genetics, gene expression analyses, chromatin immunoprecipitation studies and luciferase reporter assays, it has been shown that IRF6 is a direct target of p63, which underlies several malformation syndromes that include cleft features, and p63 activates IRF6 transcription through the IRF6 enhancer element. Variation in the enhancer element increases susceptibility to cleft lip only. Bothcleft lipwith or without acleft palateand cleft palate only features have been seen in families with an IRF6 mutation. In addition, different types of clefts can segregate within the same family.[11]

Epigenetics[edit]

The IRF6 aberrant promoterDNA hypermethylationhas been observed associated with cancer onset/progression. Indeed, this improperepigeneticphenomenon has been observed in women affected byVulvar Squamous cell carcinomaarose fromvulver lichen sclerosus.[18]Methylation of the IRF6 promoter may be a marker of cancer risk in patients affected by this disease.[8]

Cancer[edit]

IRF6 gene has been observed progressively downregulated inHuman papillomavirus-positiveneoplastic keratinocytesderived from uterine cervicalpreneoplastic lesionsat different levels of malignancy.[19]For this reason, this gene is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervicalpreneoplastic lesionsprogression.[19]Similarly, IRF6 has been found to be genetically and epigenetically disregulated inVulvar cancer.[8]

See also[edit]

References[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000117595–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000026638–Ensembl,May 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.
  5. ^abKondo 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 (October 2002)."Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes".Nat. Genet.32(2): 285–9.doi:10.1038/ng985.PMC3169431.PMID12219090.
  6. ^"Entrez Gene: IRF6".
  7. ^Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT (September 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.PMID16096995.S2CID25084563.
  8. ^abcRotondo 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.PMID27223861.
  9. ^Van der Woude, A (June 1954)."Fistula labii inferioris congenita and its association with cleft lip and palate".Am. J. Hum. Genet.6(2): 244–56.PMC1716548.PMID13158329.
  10. ^Gorlin RJ, Sedano HO, Cervenka J (February 1968). "Popliteal pterygium syndrome. A syndrome comprising cleft lip-palate, popliteal and intercrural pterygia, digital and genital anomalies".Pediatrics.41(2): 503–9.doi:10.1542/peds.41.2.503.PMID4384166.S2CID245138568.
  11. ^abDixon MJ, Marazita ML, Beaty TH, Murray JC (March 2011)."Cleft lip and palate: understanding genetic and environmental influences".Nat. Rev. Genet.12(3): 167–78.doi:10.1038/nrg2933.PMC3086810.PMID21331089.
  12. ^Little HJ, Rorick NK, Su LI, Baldock C, Malhotra S, Jowitt T, Gakhar L, Subramanian R, Schutte BC, Dixon MJ, Shore P (November 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.PMC2638798.PMID19036739.
  13. ^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.PMC2789395.PMID19282774.
  14. ^Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, Shore P, Whitmarsh A, Dixon MJ (November 2006). "Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch".Nat. Genet.38(11): 1329–34.doi:10.1038/ng1894.PMID17041603.S2CID13102953.
  15. ^Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M, Murray JC, Schutte BC (November 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.PMC2082114.PMID17041601.
  16. ^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"(PDF).N. Engl. J. Med.351(8): 769–80.doi:10.1056/NEJMoa032909.PMID15317890.
  17. ^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 (November 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.PMC2691688.PMID18836445.
  18. ^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.PMID27223861.
  19. ^abRotondo 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.hdl:11392/2066612.PMID25205602.S2CID24986454.

External links[edit]

This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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