Interferon regulatory factor 6 also known as IRF6 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''IRF6''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Function

This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly conserved

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain. The function of IRF6 is related to the formation of

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

, for example that of the

palate The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity. A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly separ ...

. This gene encodes a member of the

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...

regulatory transcription factor (IRF) family. In addition, it has been observed that IRF6 gene is under epigenetic regulation by promoter

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...

Pathology

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

of the IRF6

can lead to the autosomal dominant

van der Woude syndrome Van der Woude syndrome (VDWS) is a genetic disorder characterized by the combination of lower lip pits, cleft lip with or without cleft palate (CL/P), and cleft palate only (CPO). The frequency of orofacial clefts ranges from 1:1000 to 1:500 birth ...

(VWS) or the related popliteal pterygium syndrome (PPS). Van der Woude syndrome can include

cleft lip and palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

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

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 A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...

with or without a

cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

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.

Epigenetics

The IRF6 aberrant promoter DNA hypermethylation has been observed associated with cancer onset/progression. Indeed, this improper

epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...

phenomenon has been observed in women affected by Vulvar Squamous cell carcinoma arose from vulver lichen sclerosus. Methylation of the IRF6 promoter may be a marker of cancer risk in patients affected by this disease.

Cancer

IRF6 gene has been observed progressively downregulated in

Human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the '' Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and r ...

-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy. For this reason, this gene is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervical preneoplastic lesions progression. Similarly, IRF6 has been found to be genetically and epigenetically disregulated in Vulvar cancer.

References

External links