title: 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.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden. Electronic address: myriam.peyrard@ki.se.
authors.forename: Myriam
authors.initials: M
authors.lastname: Peyrard-Janvid
authors.affiliation: Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Leslie
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Youssef A
authors.initials: YA
authors.lastname: Kousa
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Smith
authors.affiliation: Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Martine
authors.initials: M
authors.lastname: Dunnwald
authors.affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, 17121 Solna, Sweden.
authors.forename: Måns
authors.initials: M
authors.lastname: Magnusson
authors.affiliation: Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lentz
authors.affiliation: Department of Biochemistry and Biophysics Science for Life Laboratory, Stockholm University, 17121 Solna, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Unneberg
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden.
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Fransson
authors.affiliation: Department of Clinical Genetics, Helsinki University Hospital, 00029 Helsinki, Finland.
authors.forename: Hannele K
authors.initials: HK
authors.lastname: Koillinen
authors.affiliation: Cleft Palate and Craniofacial Center, Department of Plastic Surgery, Helsinki University Hospital, 00029 Helsinki, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Rautio
authors.affiliation: Department of Orthodontics, Stockholm Craniofacial Team, Institute of Odontology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Pegelow
authors.affiliation: Department of Orthodontics, Stockholm Craniofacial Team, Institute of Odontology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Karsten
authors.affiliation: 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.
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.affiliation: Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: William
authors.initials: W
authors.lastname: Gordon
authors.affiliation: Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Bogi
authors.initials: B
authors.lastname: Andersen
authors.affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, 17121 Solna, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Svensson
authors.affiliation: Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cornell
authors.affiliation: 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.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schutte
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology*; D000483:Alleles; D000818:Animals; D002971:Cleft Lip / Q000235:genetics / Q000473:pathology*; D002972:Cleft Palate / Q000235:genetics / Q000473:pathology*; D003560:Cysts / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006801:Humans; D006824:Hybridization, Genetic; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008046:Lip / Q000002:abnormalities* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D014157:Transcription Factors