A novel mutation in IRF6 resulting in VWS-PPS spectrum disorder with renal aplasia

Department of Plastic and Reconstructive Surgery and Burns Unit, University Hospital of Copenhagen, Rigshospitalet, Denmark.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2008; 146A(12):1605-8. DOI: 10.1002/ajmg.a.32257
Source: PubMed


Popliteal pterygium syndrome (PPS) and Van der Woude syndrome (VWS) are caused by mutations in the gene interferon regulatory factor 6 (IRF6). Skeletal, genital malformations and involvement of the skin occur in PPS and orofacial clefting and lip pits occur in both. We report on a patient with unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits, unilateral renal aplasia, and a coronal hypospadias. By sequencing IRF6, we detected a novel missense mutation (Arg339Ile). The other family members were unaffected and had no IRF6 mutations, including the patient's brother who was also born with hypospadias. The patient and his brother were both conceived by in vitro fertilization (IVF). It is discussed whether the renal malformation in the patient is related to the IVF procedure or to the IRF6 mutation.

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    • "These genes include (I) genes linked to spermatogenesis with e.g. CAMK4 encoding calcium/calmodulin-dependent protein kinase IV [50] or CA2 encoding carbonic anhydrase II [51] (II) genes associated with hypospadias like IRF6 encoding interferon regulatory factor 6 [52] or (III) genes involved in prostate biology like MGMT encoding O-6-methylguanine-DNA methyltransferase [53] or TMEPAI encoding transmembrane prostate androgen-induced RNA [54]. In addition, this list includes genes associated with androgen function, including genes linked to androgen receptor co-regulators like AATF (Apoptosis-antagonising transcription factor) [55] or CDC2L2 (cell division control like 2, CDK11-p58) [56], to androgen targets like ALDH1A3 (aldehyde dehydrogenase 1A3) [57], CA2, FMO2 (Flavin-containing monooxygenase) [58] or TEMEPAI, and eventually androgen programming (HOXA5) [59]. "
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    ABSTRACT: Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.
    PLoS ONE 09/2013; 8(9):e73288. DOI:10.1371/journal.pone.0073288 · 3.23 Impact Factor
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    • "In contrast, little is known about the function of ZNRF3. Although well studied in Van der Woude syndrome, little is known about the role of IRF6 in cancer (Kondo et al., 2002; Wang et al., 2003; de Medeiros et al., 2008). In normal breast tissue, increased expression of IRF6 has been shown to induce mRNA expression of the tumor suppressor gene Maspin (Bailey and Hendrix, 2008). "
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    ABSTRACT: Asbestos-related lung cancer accounts for 4-12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos-related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC-AC: asbestos-related lung cancer-adenocarcinoma) with 24 patients with no asbestos bodies (NARLC-AC: non-asbestos related lung cancer-adenocarcinoma). Genes differentially expressed between ARLC-AC and NARLC-AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT-PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.
    Genes Chromosomes and Cancer 08/2010; 49(8):688-98. DOI:10.1002/gcc.20779 · 4.04 Impact Factor
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    • "About 70% of VWS-affected individuals carry a mutation in the interferon regulatory factor 6 (IRF6) gene that is located in the critical region of the 1q32–q41 (Kondo et al., 2002). In addition to the single-nucleotide polymorphism (SNP) G820A, which shows G (ancestral allele) as the risk allele (Zucchero et al., 2004), nearly 100 mutations in the coding region of the gene have been reported in VWS cases in populations from different parts of the globe (Kondo et al., 2002; Wang et al., 2005; Du et al., 2006; Matsuzawa et al., 2006; Brosch et al., 2007; Zechi-Ceide et al., 2007; de Medeiros et al., 2008; Tan et al., 2008). In recent years, IRF6 mutations have been offered as diagnostic and predictive tools for VWS and nonsyndromic cleft lip and/ or palate in the United States. "
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    ABSTRACT: Evaluation of the IRF6 gene in Van der Woude syndrome cases from an Indian population. Nine affected and four unaffected individuals from seven families with Van der Woude syndrome as well as five normal controls (with no history of Van der Woude or any other congenital malformation and belonging to the same geographical area as the families with Van der Woude syndrome). Direct sequencing of all coding regions and exon-intron boundaries of the IRF6 gene. Five novel variants: IVS1+3900 A>G, 191 T>C, IVS4+775 C>T, IVS8+218 C>T, 1511 T>A (Ser 416 Arg) and two known variants: IVS6+27 C>G, 1083 G>A (V274I) were detected. Except for one, all were in noncoding regions either in 3'UTR or in introns. There was only one mutation in the coding region, detected in a normal control. The present report indicates that point mutations in the coding region of the IRF6 gene may not be a major cause of Van der Woude syndrome in Indian populations.
    The Cleft Palate-Craniofacial Journal 09/2009; 46(5):541-4. DOI:10.1597/08-202.1 · 1.20 Impact Factor
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