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

Am J Hum Genet. 2014 Jan 2;94(1):23-32. doi: 10.1016/j.ajhg.2013.11.009.

Myriam Peyrard-Janvid ¹, Elizabeth J Leslie ², Youssef A Kousa ³, Tiffany L Smith ⁴, Martine Dunnwald ², Måns Magnusson ⁵, Brian A Lentz ², Per Unneberg ⁶, Ingegerd Fransson ⁷, Hannele K Koillinen ⁸, Jorma Rautio ⁹, Marie Pegelow ¹⁰, Agneta Karsten ¹⁰, Lina Basel-Vanagaite ¹¹, William Gordon ¹², Bogi Andersen ¹², Thomas Svensson ⁵, Jeffrey C Murray ², Robert A Cornell ⁴, Juha Kere ¹³, Brian C Schutte ¹⁴

Affiliations

1 Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden. Electronic address: myriam.peyrard@ki.se.
2 Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
3 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
5 Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, 17121 Solna, Sweden.
6 Department of Biochemistry and Biophysics Science for Life Laboratory, Stockholm University, 17121 Solna, Sweden.
7 Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden.
8 Department of Clinical Genetics, Helsinki University Hospital, 00029 Helsinki, Finland.
9 Cleft Palate and Craniofacial Center, Department of Plastic Surgery, Helsinki University Hospital, 00029 Helsinki, Finland.
10 Department of Orthodontics, Stockholm Craniofacial Team, Institute of Odontology, Karolinska Institutet, 17177 Stockholm, Sweden.
11 Pediatric Genetics Unit, Schneider Children's Medical Center of Israel and Raphael Recanati Genetic Institute, Rabin Medical Center, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Felsenstein Medical Research Center, Petah Tikva 49100, Israel.
12 Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
13 Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden; Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, 17121 Solna, Sweden; Research Programs Unit, University of Helsinki, and Folkhälsan Institute of Genetics, 00014 Helsinki, Finland. Electronic address: juha.kere@ki.se.
14 Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.

PMID: 24360809 DOI: 10.1016/j.ajhg.2013.11.009

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.

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