Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Abstract

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.

Interferon regulatory factor 6 regulates keratinocyte migration

“…Mice that lack grainy-head like 3 (Grhl3) are particularly relevant because, like Irf6, Grhl3 encodes a transcription factor that is required to regulate epidermal proliferation and differentiation (Yu et al, 2006). In humans, mutations in IRF6 and GRHL3 have both been identified in VWS (Kondo et al, 2002;Peyrard-Janvid et al, 2014). In addition, embryos lacking Grhl3 fail to close an ex vivo wound, and Grhl3-deficient keratinocytes were delayed in closing an in vitro scratch wound (Caddy et al, 2010;Hislop et al, 2008).…”

A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

“…Grhl3 deletion leads to decreased expression of a number of genes critical for barrier formation, including those encoding lipid processing enzymes, cell-cell adhesion molecules, and structural proteins (16). In humans, dominant-negative GRHL3 mutations are associated with defective periderm development in Van der Woude syndrome (20). In contrast to its critical role in initial epidermal formation, Grhl3 appears to be dispensable for epidermal differentiation during adult skin homeostasis (14).…”

Syndromale und nichtsyndromale orofaziale Spalten

“…70 % der Patienten findet sich eine Mutation im IRF6-Gen, deutlich seltener (ca. 5 % der Patienten) im GRHL3-Gen [22].…”