Dominant mutations in GRHL3 cause Van der Woude syndrome and disrupt oral periderm development

Myriam Peyrard-Janvid*, Elizabeth J. Leslie, Youssef A. Kousa, Tiffany L. Smith, Martine Dunnwald, Måns Magnusson, Brian A. Lentz, Per Unneberg, Ingegerd Fransson, Hannele K. Koillinen, Jorma Rautio, Marie Pegelow, Agneta Karsten, Lina Basel-Vanagaite, William Gordon, Bogi Andersen, Thomas Svensson, Jeffrey C. Murray, Robert A. Cornell, Juha KereBrian C. Schutte

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


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.

Original languageEnglish
Pages (from-to)23-32
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - 2 Jan 2014


FundersFunder number
National Institutes of HealthDE021071, DE08559, DE13513, AR44882, F31DE022696, AR061586
National Institute of General Medical SciencesT32GM008629
Vetenskapsrådet2009-5091, 521-2007-3133
Sigrid Juséliuksen Säätiö


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