HGNC Approved Gene Symbol: IRF6
SNOMEDCT: 718222000;
Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38) : 1:209,785,617-209,806,142 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.2 | {Orofacial cleft 6} | 608864 | Autosomal dominant | 3 |
| Popliteal pterygium syndrome 1 | 119500 | Autosomal dominant | 3 | |
| van der Woude syndrome 1 | 119300 | Autosomal dominant | 3 |
Interferon regulatory factor-6 (IRF6) belongs to a family of transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain termed SMIR (SMAD (see 601366)-IRF-binding domain) (summary by Kondo et al., 2002).
Kondo et al. (2002) cloned human IRF6. The deduced protein contains an N-terminal winged-helix DNA-binding domain and a C-terminal SMIR domain. RT-PCR analysis showed that Irf6 is broadly expressed in embryonic and adult mouse tissues. A similar expression pattern was seen in human fetal and adult tissues. In situ hybridization of mouse embryos demonstrated that Irf6 is highly expressed in the medial edges of the paired palatal shelves immediately before, and during, their fusion. High Irf6 expression was also detected in hair follicles, palatal rugae, tooth germ and thyroglossal duct, external genitalia, and in skin throughout the body.
Ben et al. (2005) determined that the human IRF6 protein contains 517 amino acids.
Kondo et al. (2002) determined that the IRF6 gene contains 10 exons. Exons 1, 2, and 10 are noncoding.
Ben et al. (2005) found strong structural conservation among human, mouse, zebrafish and Fugu Irf6 orthologs, especially in the 7 coding exons.
Kondo et al. (2002) identified the IRF6 gene within the VWS critical region at 1q32-q41.
Mutation in the IRF6 gene can cause van der Woude syndrome (VWS1; 119300) and popliteal pterygium syndrome (PPS; 119500). VWS is an autosomal dominant form of cleft lip and palate associated with lip pits, and is the most common syndromic form of cleft lip or palate. PPS is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data had suggested that these 2 disorders are allelic. To correlate the expression of IRF6 with the phenotypes of VWS and PPS, Kondo et al. (2002) conducted expression analyses in mice. Studies showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia, and skin. Their observations demonstrated that haploinsufficiency of IRF6 disrupts orofacial development and were consistent with dominant-negative mutations disturbing development of the skin and genitalia.
Bailey and Hendrix (2008) reported that total IRF6 protein levels increase during cell cycle arrest in cultured mammary epithelial cells, with nonphosphorylated IRF6 the prominent isoform; however, as the cell cycle initiates, IRF6 is phosphorylated and subsequently ubiquitinated and degraded, resulting in a decreased level of total IRF6 protein. IRF6 was also found to interact with maspin (154790) and, with this interaction, the regulation of IRF6 expression through phosphorylation likely regulates mammary epithelial cell differentiation by promoting exit from the cell cycle and entry into the G(0) state of differentiated quiescence.
Little et al. (2009) determined the DNA sequence to which IRF6 binds and used this sequence to analyze the effect of VWS- and PPS-associated missense mutations (see, e.g., 607199.0004) in the DNA-binding domain of IRF6. They showed that IRF6 functions as a cooperative transcriptional activator and that mutations in the protein interaction domain (residues 226 to 467) of IRF6 disrupt this activity.
Using transcriptional profiling, Moretti et al. (2010) found that endogenous Irf6 is a direct p63 (603273) target in human and mouse keratinocytes. Further analysis demonstrated that Irf6 expression is dependent on p63. IRF6 induced downregulation of p63 in human primary keratinocytes, which correlated with their differentiation. Investigation with disease-related mutations in either p63 or IRF6 in knockin mice or human keratinocytes showed that the mutants were unable to establish such a reciprocal relationship between IRF6 and p63 protein expression. IRF6 overexpression resulted in marked reduction of colony formation efficiency in epithelial cells, which was restored by coexpression of IRF6 with mutant, but not wildtype, p63, suggesting that inhibition of epithelial cell growth requires downregulation of p63. Transduction of human primary keratinocytes with retroviruses expressing IRF6 confirmed that IRF6 expression reduces the proliferative potential of epidermal cells.
Kwa et al. (2015) expressed human IRF6 protein truncated at arg412, a mutation identified in Van der Woude syndrome (VWS), in HEK293T cells and found that the truncation did not affect the cytoplasmic localization of IRF6, but resulted in reduced expression levels of the protein due to accelerated proteasome-dependent degradation. Coexpression of Ripk4 (605706), which phosphorylates and activates IRF6, with truncated IRF6 in HEK293T cells did not significantly increase transactivator function, likely because of the absence of ser413 and ser424 regulatory phosphorylation sites in the truncated protein.
Oberbeck et al. (2019) showed that the role of RIPK4 (605706) in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biologic processes; and that the phosphorylation of IRF6 at ser413 and ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wildtype and IRF6-deficient mouse embryos, Oberbeck et al. (2019) defined the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-null skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Oberbeck et al. (2019) concluded that their results explained how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provided mechanistic insights into why developmental syndromes that are characterized by orofacial, skin, and genital abnormalities result when this axis goes awry.
Van der Woude Syndrome
To identify the locus associated with van der Woude syndrome (119300), Kondo et al. (2002) did a direct sequence analysis of genes and presumptive transcripts in the 350-kb critical region on 1q identified by linkage mapping. This approach was confounded by SNPs that occurred about once every 1,900 basepairs. To distinguish between putative disease-causing mutations and SNPs, they studied a pair of monozygotic twins who were discordant for the VWS phenotype and had unaffected parents. Monozygotic status was confirmed by showing complete concordance of genotype at 20 microsatellite loci. The authors concluded that the only sequence difference between the twins resulted from a somatic mutation in the affected twin. Kondo et al. (2002) found a nonsense mutation in IRF6 in the affected twin (607199.0001). Subsequently, they identified mutations in IRF6 in 45 additional unrelated families affected with VWS.
Ghassibe et al. (2004) screened the IRF6 gene in 6 families with VWS and identified 6 heterozygous missense mutations, respectively, all affecting either the DNA-binding or the protein-binding domain. In a 4-generation VWS family in which affected individuals carried an L22P mutation (607199.0014), 2 of the patients displayed additional features: 1 had finger syndactyly, and the other had toe syndactyly and oral synechiae. Ghassibe et al. (2004) stated that because syndactyly and synechiae are major signs for PPS, these 2 patients were considered to have PPS, whereas the 6 other affected family members were classified as VWS, thus demonstrating that a single mutation could be responsible for both syndromes.
In a 16-year-old girl with a heart-shaped mass on her inner lower lip but no pits, Yeetong et al. (2009) identified heterozygosity for a nonsense mutation in the IRF6 gene (Q49X; 607199.0017).
Malik et al. (2010) identified IRF6 mutations in 12 of 16 Pakistani VWS probands (see, e.g., 607199.0009 and 607199.0018), including 2 missense mutations that previously had been identified in patients with popliteal pterygium syndrome (PPS). While no clinical signs of PPS were identified or reported by these patients or their families, Malik et al. (2010) noted that subtler signs of PPS such as genital hypoplasia may have been present but were not evaluated in this study.
To test whether DNA variants in regulatory elements cause VWS, Fakhouri et al. (2014) sequenced 3 conserved elements near IRF6 in 70 VWS families who were negative for mutations with IRF6 exons. In a 3-generation Brazilian family, the authors identified a duplication (350dupA) within a highly conserved sequence in the MCS9.7 enhancer element. The duplication was present in 3 affected individuals as well as in 2 unaffected family members, but it was not found in 100 unaffected controls or in 1,092 genomes from 14 populations in the NHLBI Exome Sequencing Project database. The 350dupA mutation abrogated binding of p63 (TP63; 603273) and E47 (TCF3; 147141) transcription factors to cis-overlapping motifs, and significantly disrupted enhancer activity in human cell cultures. In a transgenic assay in mice, the 350dupA mutation disrupted activation of the MSC9.7 enhancer element and resulted in failure of lacZ expression in all head and neck pharyngeal arches. Fakhouri et al. (2014) noted that 350dupA creates a CAAAGT motif, a binding site for Lef1 (153245) protein; the authors also demonstrated both that Lef1 binds to the mutated site and that overexpression of a Lef1/beta-catenin (CTNNB1; 116806) chimeric protein represses mutant MCS9.7 enhancer activity.
Popliteal Pterygium Syndrome
In affected members of 5 unrelated families with popliteal pterygium syndrome (PPS; 119500), Kondo et al. (2002) identified heterozygosity for an arg84-to-cys (R84C; 607199.0004) mutation in the IRF6 gene. In 2 other PPS families, they identified an arg84-to-his (R84H; 607199.0005) substitution.
Matsuzawa et al. (2010) identified a heterozygous R84L mutation (607199.0015) in a Japanese family with variable expression of popliteal-pterygium syndrome. Mutations in the same codon, R84C and R84H, have been reported in other patients with PPS (Kondo et al., 2002), suggesting a hotspot for recurrent mutations.
Van der Woude Syndrome-Popliteal Pterygium Syndrome Spectrum
De Medeiros et al. (2008) described a patient, conceived by in vitro fertilization, with unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits, unilateral renal aplasia, and a coronal hypospadias, with a novel heterozygous mutation (607199.0013) in the IRF6 gene. The authors considered the patient to have a VWS-PPS spectrum disorder. They were uncertain whether renal aplasia was related to the mutation or the method of fertilization.
Orofacial Cleft 6
Zucchero et al. (2004) found overtransmission of the ancestral allele of the V274I polymorphism (rs2235371), originally identified by Kondo et al. (2002), in patients with nonsyndromic cleft lip and palate (OFC6; 608864) who were Asian but not in groups of European descent. Zucchero et al. (2004) noted that their findings suggested that the V allele itself was not causal.
Rahimov et al. (2008) used multispecies sequence comparison to identify a common SNP (rs642961, G-A) in an IRF6 enhancer located in the intergenic region between the start sites of the oppositely transcribed IRF6 and C1ORF107 genes (genome coordinate 208,055,893; build 36.3). They found that the A allele was significantly overtransmitted (p = 1 x 10(-11)) in families with nonsyndromic cleft lip/palate (OFC6; 608864), particularly in those with cleft lip only. EMSA and CHIP assays demonstrated that the risk allele disrupts the binding site of transcription factor AP-2-alpha (TFAP2A; 107580), and expression analysis in the mouse localized the enhancer activity to craniofacial and limb structures. In luciferase reported assays in a human foreskin keratinocyte cell line, the risk haplotype consistently increased the luciferase expression more than the nonassociated haplotypes did, but the difference did not reach statistical significance. Rahimov et al. (2008) concluded that IRF6 and TFAP2A are in the same developmental pathway and that this high frequency variant, located within the MCS9.7 regulatory element, contributes substantially to a common, complex disorder.
Clefts of the lip with or without cleft palate and isolated cleft palate are developmentally and genetically distinct (see 119530 and 119540, respectively), yet VWS is a single-gene disorder that encompasses both clefting phenotypes. To verify this point, Kondo et al. (2002) analyzed 22 pedigrees that had a single mutation in IRF6 and individuals with both phenotypes. Genotype analysis of 1 family demonstrated that affected individuals, regardless of their phenotype, shared the deletion (607199.0002) that occurred in the proband. They observed similar results in the other families and concluded that a single mutation in IRF6 can cause both types of clefting. Protein-truncation mutations were significantly more common in VWS than in PPS (P = 0.004). The lone exception was a nonsense mutation present in 1 family, glu393 to ter (607199.0003), which may be a dominant-negative mutation.
Kondo et al. (2002) found that missense mutations that cause VWS were almost evenly divided between the DNA-binding domain and the protein-binding domain, whereas most missense mutations that cause PPS were found in the DNA-binding domain. Comparison of the positions of PPS mutations with the crystal structure of the IRF1 DNA-binding domain showed that every amino acid residue that was mutant in individuals with PPS directly contacts the DNA, whereas only 1 of 7 of the residues mutant in individuals with VWS contacts the DNA. Most notably, Kondo et al. (2002) observed missense mutations involving the arg84 codon in 7 unrelated PPS families. The arg84 residue is comparable to the arg82 residue of IRF1. Variation in the phenotypic effects of mutations in the IRF6 gene causing VWS and PPS suggested the operation of stochastic factors or modifier genes influencing IRF6 function. Three sorts of variation were observed. Thirty-two families had multiple combinations of orofacial anomalies, 22 families had mixed clefting phenotypes (individuals with cleft lip and individuals with cleft palate only in the same family), and 4 families affected with PPS included individuals who exhibited orofacial (VWS) features exclusively. Kondo et al. (2002) identified a sequence variant, val274 to ile, occurring within an absolutely conserved residue within the SMIR domain. This variant is common in unaffected populations (3% in European-descended and 22% in Asian populations) and was considered by them an attractive candidate for a modifier of VWS, PPS, and other orofacial clefting disorders.
The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population. Richardson et al. (2006) undertook a study of the signals controlling the proliferation-differentiation switch in vivo. They showed that mice carrying a homozygous missense mutation in Irf6, the homolog of the gene mutated in the human congenital disorders van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. They further demonstrated that mice compound heterozygous for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (SFN; 601290) show similar defects of keratinizing epithelia. The results indicated that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.
Ingraham et al. (2006) obtained Irf6-null mice at the expected mendelian ratio. At embryonic day 17.5, Irf6-null mice had taut, shiny skin, lacked external ears, and had snouts and jaws shorter and more rounded than their wildtype littermates. Irf6-null embryos also had short forelimbs that lacked visible digits and a single caudal projection that lacked visible hindlimbs and tail. Histologic and gene expression analyses showed that the primary defect was in keratinocyte differentiation and proliferation. Ingraham et al. (2006) found that abnormalities of epithelial differentiation that resulted in cleft palate were a consequence of adhesion between the palatal shelves and the tongue in both Irf6-null and homozygous missense mice.
Richardson et al. (2009) showed that Irf6/Jag2 (602570) doubly heterozygous mice displayed a fully penetrant intraoral epithelial adhesions, resulting in cleft palate. There was no evidence of direct interaction between Irf6 and Jag2, suggesting that the mechanism underlying the genetic interaction between Irf6 and Jag2 is the consequence of their combined effects on periderm formation, maintenance, and function. Notch1 (190198) and p63 (603273) expression patterns in Irf6/Jag2 doubly heterozygous mouse embryos suggested that Irf6 affects Jag2-Notch1 signaling during periderm maintenance.
In the affected twin of a pair of monozygotic twins who were discordant for van der Woude syndrome (VWS1; 119300), Kondo et al. (2002) found a nonsense mutation in exon 4 of the IRF6 gene that was absent in both parents and the unaffected twin: glu92 to ter (E92X).
In affected members of a family with van der Woude syndrome (VWS1; 119300), Kondo et al. (2002) identified heterozygosity for an 19-bp deletion (CACTAGCAAGCTGCTGGAC) and insertion of a single adenine occurring after nucleotide 870 of the IRF6 gene. Some affected members had cleft of the lip with cleft palate, others had cleft of the lip without cleft palate, and yet others had isolated cleft plate; regardless of the phenotype, all shared the deletion found in the proband. The authors referred to the mutation as an 18-bp deletion and gave the resulting amino acid change as FTSKLLD290L.
Kondo et al. (2002) found that protein-truncation mutations of the IRF6 gene were significantly more common in van der Woude syndrome (VWS; 119300) than in popliteal pterygium syndrome (PPS; 119500) (P = 0.004). The lone exception to this relationship was a nonsense mutation introducing a stop codon in place of a glutamine codon at position 393 (Q393X), which may be a dominant-negative mutation, found in affected members of a PPS family.
In affected members of 5 unrelated families with popliteal pterygium syndrome (PPS; 119500), Kondo et al. (2002) identified heterozygosity for a 250C-T transition in the IRF6 gene resulting in an arg84-to-cys (R84C) change in the protein. In affected members of 2 other PPS families, arg84 was changed to a different amino acid (607199.0005).
In affected members of 2 unrelated families with PPS (119500), Kondo et al. (2002) found an arg84-to-his (R84H) missense mutation in the IRF6 gene. The arg84 residue, affected in the arg84-to-cys (607199.0004) and arg84-to-his missense mutations, is 1 of 4 residues that make critical contacts with the core sequence, GAAA, and is essential for the DNA binding function of IRF6.
Wang et al. (2003) screened 4 Chinese families with van der Woude syndrome (VWS1; 119300) in 9 exons and their flanking splice junctions of the IRF6 gene by direct sequencing. They identified 3 missense mutations, including ala2-to-val (A2V), resulting from a 268C-T nucleotide change. The A2V mutation had been reported previously in an American family by Kondo et al. (2002).
In a Chinese family with van der Woude syndrome (VWS1; 119300), Wang et al. (2003) identified a 279C-T transition in exon 3 of the IRF6 gene, resulting in an arg6-to-cys (R6C) substitution.
In a Chinese family with van der Woude syndrome (VWS1; 119300), Wang et al. (2003) found a nonsense mutation in the IRF6 gene: a TGG-to-TGA (1400G-A) transition in exon 8, introducing a premature stop codon in place of a tryptophan residue (W379X).
In a Chinese family with van der Woude syndrome (VWS1; 119300), Wang et al. (2003) found that affected members carried a missense mutation in the IRF6 gene: a 1461C-T transition in exon 9, predicting a tryptophan substitution for a highly conserved arginine at codon 400 (R400W).
In affected members of a large 4-generation Pakistani family with VWS, Malik et al. (2010) identified heterozygosity for the R400W mutation in the IRF6 gene. Thirteen family members exhibited cleft lip, 1 of whom also had lower lip pits; 2 other family members had lower lip pits alone.
In a Japanese family with van der Woude syndrome (VWS1; 119300), Kayano et al. (2003) found a 17-kb deletion in the IRF6 gene. On initial sequencing no base change was found, but a deletion involving exons 4-9 was suggested by multiplex PCR analysis. Further analyses revealed a heterozygous 17,162-bp deletion involving exons 4-9. Kayano et al. (2003) suggested that since IRF6 mutations in a significant portion of VWS patients remain undetected by conventional sequencing analysis, it may be important to search for a large deletion in such patients.
In a Japanese family with van der Woude syndrome (VWS1; 119300), Kayano et al. (2003) found a heterozygous 134G-A transition in exon 3 of the IRF6 gene that resulted in an arg45-to-gln (R45Q) substitution.
In a Japanese family with van der Woude syndrome (VWS1; 119300), Kayano et al. (2003) found a heterozygous 1186C-T transition in exon 9 of the IRF6 gene that resulted in a pro396-to-ser (P396S) amino acid change.
In a patient with overlapping features of van der Woude syndrome (VWS1; 119300) and popliteal pterygium syndrome (PPS; 119500) (unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits) as well as unilateral renal aplasia and coronal hypospadias, de Medeiros et al. (2008) identified heterozygosity for a 1016G-T transversion in the IRF6 gene, resulting in an arg339-to-ile (R339I) substitution. The mutation was not found in 60 unrelated control individuals. The patient and his brother, who had hypospadias and nephrocalcinosis but no IRF6 mutation, were both conceived by in vitro fertilization. De Medeiros et al. (2008) suggested that the hypospadias and renal aplasia may have been due to the method of fertilization rather than the IRF6 mutation. They noted that a lethal PPS syndrome (263650) has renal aplasia as a feature.
In affected individuals from a 4-generation family with van der Woude syndrome (VWS1; 119300), Ghassibe et al. (2004) identified heterozygosity for a 65T-C transition in exon 3 of the IRF6 gene, resulting in a leu22-to-pro (L22P) substitution in the DNA-binding domain. In addition to lip pits and clefting, 2 of the patients also had syndactyly and synechiae, major signs for popliteal-pterygium syndrome (PPS; 119500). Ghassibe et al. (2004) stated that these 2 patients were considered to have PPS, whereas the 6 other affected family members were classified as VWS, thus demonstrating that a single mutation could be responsible for both syndromes.
In a Japanese boy with popliteal-pterygium syndrome (PPS; 119500), Matsuzawa et al. (2010) identified a heterozygous 251G-T transversion in exon 4 of the IRF6 gene, resulting in an arg84-to-leu (R84L) substitution in a critical site for DNA binding. The boy had lip pits, bilateral cleft lip and palate, syngnathia, syndactyly, popliteal webbing, and atrophic testes. His father, who also carried the mutation, had bilateral cleft lip and palate only. Family history revealed a paternal grandfather and aunt with bifid uvula and cleft palate. Thus, variable expressivity was clinically evident in this family. The mutation was not detected in the mother or in 90 healthy Japanese controls. The R84C (607199.0004) and R84H (607199.0005) mutations in the same codon were previously reported by Kondo et al. (2002) in other patients with PPS, suggesting a hotspot for recurrent mutations.
In a Japanese boy and his mother with PPS (119500), Matsuzawa et al. (2010) identified a heterozygous 1271C-T transition in exon 9 of the IRF6 gene, resulting in a ser424-to-leu (S424L) substitution. The mutation was not found in 200 Japanese controls. In vitro functional expression studies showed that the mutant protein had 6% residual activity, consistent with a loss of function. The boy had cleft palate, syngnathia, unclear scrotum, syndactyly, and mild popliteal webbing, whereas his mother had cleft lip and palate, syngnathia, syndactyly, and hypoplasia of the labia majora.
In a 16-year-old girl with a heart-shaped mass on her inner lower lip (VWS1; 119300) but no pits, oral clefts, or hypodontia, Yeetong et al. (2009) identified heterozygosity for a 145C-T transition in exon 3 of the IRF6 gene, resulting in a gln49-to-ter (Q49X) substitution in the highly conserved DNA-binding domain. Her mother and other relatives were reported to have similar findings, but were unavailable for evaluation.
In affected members of a large 3-generation Pakistani family with VWS1 (119300), Malik et al. (2010) identified heterozygosity for a c.1199G-A transition in exon 9 of the IRF6 gene, resulting in an arg400-to-gln (R400Q) substitution at a highly conserved residue. In this family, 5 patients had CL/P, of whom 3 also displayed lip pits; 3 patients had CL, of whom 1 also had lip pits; and 4 individuals had lip pits alone.
In a patient with a clinical diagnosis of popliteal pterygium syndrome (PPS; 119500), Leslie et al. (2015) identified a homozygous c.1316T-C transition (c.1316T-C, NM_006147.3) in exon 9 of the IRF6 gene, resulting in a leu439-to-pro (L439P) substitution at a highly conserved residue in the protein-binding domain. Both parents were heterozygous for the mutation, which was not found in the 1000 Genomes Project or Exome Sequencing Project databases. The proband was a 9-day-old neonate, born to consanguineous parents, with multiple congenital malformations including adhesions between left eyelids (ankyloblepharon), bilateral cleft lip, cleft of the hard palate, lower lip pit, a band of soft tissue connecting lower lip and palate, pterygia of popliteal fossae (more severe on the left than the right), bilateral clubfoot, and syndactyly of all 4 toes on both feet. Clinical examination of the mother and sister showed a short frenulum, but the father was normal. No lip pits, hypodontia, or palatal defects were noted in the parents. The authors hypothesized that L439P is a hypomorphic allele, providing less than the equivalent of 1 functional IRF6 allele and resulting in a more severe phenotype in the proband and no discernable phenotype in the parents.
Bailey, C. M., Hendrix, M. J. C. IRF6 in development and disease: a mediator of quiescence and differentiation. Cell Cycle 7: 1925-1930, 2008. [PubMed: 18604160] [Full Text: https://doi.org/10.4161/cc.7.13.6221]
Ben, J., Jabs, E. W., Chong, S. S. Genomic, cDNA and embryonic expression analysis of zebrafish IRF6, the gene mutated in the human oral clefting disorders Van der Woude and popliteal pterygium syndromes. Gene Expr. Patterns 5: 629-638, 2005. [PubMed: 15939375] [Full Text: https://doi.org/10.1016/j.modgep.2005.03.002]
de Medeiros, F., Hansen, L., Mawlad, E., Eiberg, H., Asklund, C., Tommerup, N., Jakobsen, L. P. A novel mutation in IRF6 resulting in VWS-PPS spectrum disorder with renal aplasia. Am. J. Med. Genet. 146A: 1605-1608, 2008. [PubMed: 18478600] [Full Text: https://doi.org/10.1002/ajmg.a.32257]
Fakhouri, W. D., Rahimov, F., Attanasio, C., Kouwenhoven, E. N., Ferreira De Lima, R. L., Felix, T. M., Nitschke, L., Huver, D., Barrons, J., Kousa, Y. A., Leslie, E., Pennacchio, L. A., Van Bokhoven, H., Visel, A., Zhou, H., Murray, J. C., Schutte, B. C. An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects. Hum. Molec. Genet. 23: 2711-2720, 2014. [PubMed: 24442519] [Full Text: https://doi.org/10.1093/hmg/ddt664]
Ghassibe, M., Revencu, N., Bayet, B., Gillerot, Y., Vanwijck, R., Verellen-Dumoulin, C., Vikkula, M. Six families with van der Woude and/or popliteal pterygium syndrome: all with a mutation in the IRF6 gene. J. Med. Genet. 41: e15, 2004. Note: Electronic Article. [PubMed: 14757865] [Full Text: https://doi.org/10.1136/jmg.2003.009274]
Ingraham, C. R., Kinoshita, A., Kondo, S., Yang, B., Sajan, S., Trout, K. J., Malik, M. I., Dunnwald, M., Goudy, S. L., Lovett, M., Murray, J. C., Schutte, B. C. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nature Genet. 38: 1335-1340, 2006. [PubMed: 17041601] [Full Text: https://doi.org/10.1038/ng1903]
Kayano, S., Kure, S., Suzuki, Y., Kanno, K., Aoki, Y., Kondo, S., Schutte, B. C., Murray, J. C., Yamada, A., Matsubara, Y. Novel IRF6 mutations in Japanese patients with van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion. J. Hum. Genet. 48: 622-628, 2003. [PubMed: 14618417] [Full Text: https://doi.org/10.1007/s10038-003-0089-0]
Kondo, S., Schutte, B. C., Richardson, R. J., Bjork, B. C., Knight, A. S., Watanabe, Y., Howard, E., Ferreira de Lima, R. L. L., Daack-Hirsch, S., Sander, A., McDonald-McGinn, D. M., Zackai, E. H., and 14 others. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. (Letter) Nature Genet. 32: 285-289, 2002. [PubMed: 12219090] [Full Text: https://doi.org/10.1038/ng985]
Kwa, M. Q., Huynh, J., Reynolds, E. C., Hamilton, J. A., Scholz, G. M. Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions. Cell. Signal. 27: 1509-1516, 2015. [PubMed: 25784454] [Full Text: https://doi.org/10.1016/j.cellsig.2015.03.005]
Leslie, E. J., O'Sullivan, J., Cunningham, M. L., Singh, A., Goudy, S. L., Ababneh, F., Alsubaie, L., Ch'ng, G.-S., van der Laar, I. M. B. H., Hoogeboom, A. J. M., Dunnwald, M., Kapoor, S., Jiramongkolchai, P., Standley, J., Manak, J. R., Murray, J. C., Dixon, M. J. Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am. J. Med. Genet. 167A: 545-552, 2015. [PubMed: 25691407] [Full Text: https://doi.org/10.1002/ajmg.a.36896]
Little, H. J., Rorick, N. K., Su, L.-I., Baldock, C., Malhotra, S., Jowitt, T., Gakhar, L., Subramanian, R., Schutte, B. C., Dixon, M. J., Shore, P. Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6. Hum. Molec. Genet. 18: 535-545, 2009. Note: Erratum: Hum. Molec. Genet. 18: 1544 only, 2009. [PubMed: 19036739] [Full Text: https://doi.org/10.1093/hmg/ddn381]
Malik, S., Kakar, N., Hasnain, S., Ahmad, J., Wilcox, E. R., Naz, S. Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan. Clin. Genet. 78: 247-256, 2010. [PubMed: 20184620] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01375.x]
Matsuzawa, N., Kondo, S., Shimozato, K., Nagao, T., Nakano, M., Tsuda, M., Hirano, A., Niikawa, N., Yoshiura, K. Two missense mutations of the IRF6 gene in two Japanese families with popliteal pterygium syndrome. Am. J. Med. Genet. 152A: 2262-2267, 2010. [PubMed: 20803643] [Full Text: https://doi.org/10.1002/ajmg.a.33338]
Moretti, F., Marinari, B., Lo Iacono, N., Botti, E., Giunta, A., Spallone, G., Garaffo, G., Vernersson-Lindahl, E., Merlo, G., Mills, A. A., Ballaro, C., Alema, S., Chimenti, S., Guerrini, L., Costanzo, A. A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias. J. Clin. Invest. 120: 1570-1577, 2010. [PubMed: 20424325] [Full Text: https://doi.org/10.1172/JCI40267]
Oberbeck, N., Pham, V. C., Webster, J. D., Reja, R., Huang, C. S., Zhang, Y., Roose-Girma, M., Warming, S., Li, Q., Birnberg, A., Wong, W., Sandoval, W., Komuves, L. G., Yu, K., Dugger, D. L., Maltzman, A., Newton, K., Dixit, V. M. The RIPK4-IRF6 signalling axis safeguards epidermal differentiation and barrier function. Nature 574: 249-253, 2019. [PubMed: 31578523] [Full Text: https://doi.org/10.1038/s41586-019-1615-3]
Rahimov, F., Marazita, M. L., Visel, A., Cooper, M. E., Hitchler, M. J., Rubini, M., Domann, F. E., Govil, M., Christensen, K., Bille, C., Melbye, M., Jugessur, A., and 11 others. Disruption of an AP-2-alpha binding site in an IRF6 enhancer is associated with cleft lip. Nature Genet. 40: 1341-1347, 2008. [PubMed: 18836445] [Full Text: https://doi.org/10.1038/ng.242]
Richardson, R. J., Dixon, J., Jiang, R., Dixon, M. J. Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence. Hum. Molec. Genet. 18: 2632-2642, 2009. [PubMed: 19439425] [Full Text: https://doi.org/10.1093/hmg/ddp201]
Richardson, R. J., Dixon, J., Malhotra, S., Hardman, M. J., Knowles, L., Boot-Handford, R. P., Shore, P., Whitmarsh, A., Dixon, M. J. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nature Genet. 38: 1329-1334, 2006. [PubMed: 17041603] [Full Text: https://doi.org/10.1038/ng1894]
Wang, X., Liu, J., Zhang, H., Xiao, M., Li, J., Yang, C., Lin, X., Wu, Z., Hu, L., Kong, X. Novel mutations in the IRF6 gene for Van der Woude syndrome. Hum. Genet. 113: 382-386, 2003. [PubMed: 12920575] [Full Text: https://doi.org/10.1007/s00439-003-0989-2]
Yeetong, P., Mahatumarat, C., Siriwan, P., Rojvachiranonda, N., Suphapeetiporn, K., Shotelersuk, V. Three novel mutations of the IRF6 gene with one associated with an unusual feature in van der Woude syndrome. Am. J. Med. Genet. 149A: 2489-2492, 2009. [PubMed: 19842205] [Full Text: https://doi.org/10.1002/ajmg.a.33048]
Zucchero, T. M., Cooper, M. E., Maher, B. S., Daack-Hirsch, S., Nepomuceno, B., Ribeiro, L., Caprau, D., Christensen, K., Suzuki, Y., Machida, J., Natsume, N., Yoshiura, K.-I., and 17 others. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. New Eng. J. Med. 351: 769-780, 2004. [PubMed: 15317890] [Full Text: https://doi.org/10.1056/NEJMoa032909]