This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain.
A mutation of the IRF6 gene can lead to the autosomal dominant van der Woude syndrome (VWS)  or the related popliteal pterygium syndrome (PPS). Van der Woude syndrome can include cleft 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. These disorders are caused by mutations in the IRF6 gene and some of the phenotypic heterogeneity is due to different types of IRF6 mutations. 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 in haploinsufficiency while PPS mutations may be dominant negative in nature. The spectrum of mutations in VWS and PPS has been recently summarized. IRF6 has been shown to play a critical role in keratinocyte development. A role for IRF6 in the common forms of cleft lip and palate has also been demonstrated and may explain ~20% of cases of cleft lip only. 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. Both cleft lip with or without a cleft 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.
- 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 (October 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.
- "Entrez Gene: IRF6".
- 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. PMID 16096995.
- 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. PMC 1716548. PMID 13158329.
- 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. PMID 4384166.
- Dixon 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. 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 (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. 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 (November 2006). "Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch". Nat. Genet. 38 (11): 1329–34. doi:10.1038/ng1894. PMID 17041603.
- 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. 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 (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. PMC 2691688. PMID 18836445.
- GeneReview/NIH/UW entry on IRF6-Related Disorders
- IRF6+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- IRF6 human gene location in the UCSC Genome Browser.
- IRF6 human gene details in the UCSC Genome Browser.