This gene encodes a member of theinterferon regulatory transcription factor (IRF) family. Family members share a highly conservedN-terminalhelix-turn-helix DNA-binding domain and a less conservedC-terminal protein-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 theinterferon regulatory transcription factor (IRF) family. In addition, it has been observed that IRF6 gene is under epigenetic regulation by promotermethylation.[8]
Amutation of the IRF6gene can 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 palate features 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 inhaploinsufficiency while PPS mutations may bedominant negative in 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 palate has 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 lip with or without acleft palate and 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]
The IRF6 aberrant promoterDNA hypermethylation has been observed associated with cancer onset/progression. Indeed, this improperepigenetic phenomenon has been observed in women affected byVulvar Squamous cell carcinoma arose fromvulver lichen sclerosus.[18] Methylation of the IRF6 promoter may be a marker of cancer risk in patients affected by this disease.[8]
IRF6 gene has been observed progressively downregulated inHuman papillomavirus-positiveneoplastic keratinocytes derived from uterine cervicalpreneoplastic lesions at 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 lesions progression.[19] Similarly, IRF6 has been found to be genetically and epigenetically disregulated inVulvar cancer.[8]
^"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.
^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.
^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.
^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.
^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.
