Dataset Information

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

ABSTRACT: Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits. Furthermore, they have an increased risk for wound-healing complications following surgical repair when compared with patients with nonsyndromic cleft lip and palate (NSCLP). However, nothing is known about the skin of these patients. The objective was to characterize the skin of patients with VWS. We hypothesize that IRF6 is required for proper skin homeostasis in humans.Discarded tissue from a hip was collected during surgical alveolar bone graft. Samples from children with VWS harboring IRF6 mutations (n = 2) were compared with samples from children with NSCLP (n = 7). Histology was assessed following hematoxylin and eosin staining. The expressions of Proliferating Cell Nuclear Antigen, IRF6, P63, and Keratin 10 were determined by immunofluorescence. Keratinocytes were isolated and their proliferation potential was assessed by colony-forming efficiency assay.Hip skin from children with VWS showed a thicker epidermis when compared with that from children with NSCLP. Proliferating Cell Nuclear Antigen staining revealed an increase in proliferation in syndromic tissues when compared with controls. However, P63 and Keratin 10 expression were similar between groups. Finally, keratinocytes from VWS showed increased long-term proliferation when compared with NSCLP.These results support, in vivo and in vitro, a previously described role for IRF6 in epidermal proliferation in humans. They further demonstrate a critical function for IRF6 in cutaneous homeostasis.

SUBMITTER: Hixon K

PROVIDER: S-EPMC5776006 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

Hixon Katherine K Rhea Lindsey L Standley Jennifer J Canady Frank J FJ Canady John W JW Dunnwald Martine M

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 20160426 3

<h4>Objective</h4>Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits. Furthermore, they have an increased risk for wound-healing complications following surgical repair when compared with patients with nonsyndromic cleft lip and palate (NSCLP). ...[more]

PMID: 27115562

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Project description:Background:Loss-of-function mutations in interferon regulatory factor-6 (IRF6) are responsible for about 70% of cases of Van Der Woude Syndrome (VWS), an autosomal dominant developmental disorder characterized by pits and/or sinuses of the lower lip and cleft lip, cleft palate, or both. Methods:We collected a Chinese Han VWS pedigree, performed sequencing and screening for the causal gene mutant. Initially, species conservation analysis and homology protein modeling were used to predict the potential pathogenicity of mutations. To test whether a VWS family-derived mutant variant of IRF6 retained function, we carried out rescue assays in irf6 maternal-null mutant zebrafish embryos. To assess protein stability, we overexpressed reference and family-variants of IRF6 in vitro. Results:We focused on a VWS family that includes a son with bilateral lip pits, uvula fissa and his father with bilateral cleft lip and palate. After sequencing and screening, a frameshift mutation of IRF6 was identified as the potential causal variant (NM.006147.3, c.1088-1091delTCTA; p.Ile363ArgfsTer33). The residues in this position are strongly conserved among species and homology modeling suggests the variant alters the protein structure. In irf6 maternal-null mutant zebrafish embryos the periderm differentiates abnormally and the embryos rupture and die during gastrulation. Injection of mRNA encoding the reference variant of human IRF6, but not of the frame-shift variant, rescued such embryos through gastrulation. Upon overexpression in HEK293FT cells, the IRF6 frame-shift mutant was relatively unstable and was preferentially targeted to the proteasome in comparison to the reference variant. Conclusion:In this VWS pedigree, a novel frameshift of IRF6 was identified as the likely causative gene variant. It is a lost function mutation which could not rescue abnormal periderm phenotype in irf6 maternal-null zebrafish and which causes the protein be unstable through proteasome-dependent degradation.

Dataset Information

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

Publications

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

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