ZFIN ID: ZDB-PUB-140220-21
Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development
Peyrard-Janvid, M., Leslie, E.J., Kousa, Y.A., Smith, T.L., Dunnwald, M., Magnusson, M., Lentz, B.A., Unneberg, P., Fransson, I., Koillinen, H.K., Rautio, J., Pegelow, M., Karsten, A., Basel-Vanagaite, L., Gordon, W., Andersen, B., Svensson, T., Murray, J.C., Cornell, R.A., Kere, J., and Schutte, B.C.
Date: 2014
Source: American journal of human genetics   94(1): 23-32 (Journal)
Registered Authors: Cornell, Robert
Keywords: none
MeSH Terms:
  • Abnormalities, Multiple/genetics
  • Abnormalities, Multiple/pathology*
  • Alleles
  • Animals
  • Cleft Lip/genetics
  • Cleft Lip/pathology*
  • Cleft Palate/genetics
  • Cleft Palate/pathology*
  • Cysts/genetics
  • Cysts/pathology*
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism
  • Gene Expression Regulation, Developmental
  • Genotype
  • Humans
  • Hybridization, Genetic
  • Interferon Regulatory Factors/genetics
  • Interferon Regulatory Factors/metabolism
  • Lip/abnormalities*
  • Lip/pathology
  • Mice
  • Mice, Knockout
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA
  • Transcription Factors/genetics*
  • Transcription Factors/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 24360809 Full text @ Am. J. Hum. Genet.

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.