IRF6

Interferon regulatory factor 6 also known as IRF6 is a is_associated_with::protein that in humans is encoded by the IRF6 is_associated_with::gene.

Function
This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly conserved N-terminal is_associated_with::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 is_associated_with::connective tissue, for example that of the is_associated_with::palate. This gene encodes a member of the is_associated_with::interferon regulatory transcription factor (IRF) family.

Pathology
A is_associated_with::mutation of the IRF6 is_associated_with::gene can lead to the autosomal dominant is_associated_with::van der Woude syndrome (VWS) or the related is_associated_with::popliteal pterygium syndrome (PPS). Van der Woude syndrome can include is_associated_with::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 is_associated_with::haploinsufficiency while PPS mutations may be is_associated_with::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 is_associated_with::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 is_associated_with::cleft lip with or without a is_associated_with::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.