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 Kere; Brian C Schutte

doi:10.1016/j.ajhg.2013.11.009

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

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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, …

American journal of human genetics, Vol.94(1), pp.23-32

01/02/2014

DOI: 10.1016/j.ajhg.2013.11.009

PMCID: PMC3882735

PMID: 24360809

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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.

Abnormalities, Multiple - pathology

Lip - abnormalities

Humans

Interferon Regulatory Factors - metabolism

Cleft Palate - genetics

Mutation, Missense

Zebrafish - embryology

DNA-Binding Proteins - metabolism

Cleft Lip - pathology

Gene Expression Regulation, Developmental

Hybridization, Genetic

Abnormalities, Multiple - genetics

Lip - pathology

Interferon Regulatory Factors - genetics

Genotype

Transcription Factors - genetics

DNA-Binding Proteins - genetics

Cysts - pathology

Sequence Analysis, DNA

Zebrafish - genetics

Mice, Knockout

Transcription Factors - metabolism

Cleft Lip - genetics

Phenotype

Animals

Pedigree

Cleft Palate - pathology

Alleles

Cysts - genetics

Mice

Details

Title: Subtitle: Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development
Creators: Myriam Peyrard-Janvid - Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden. Electronic address: myriam.peyrard@ki.se
Elizabeth J Leslie - Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
Youssef A Kousa - Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
Tiffany L Smith - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Martine Dunnwald - Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
Måns Magnusson - Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, 17121 Solna, Sweden
Brian A Lentz - Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
Per Unneberg - Department of Biochemistry and Biophysics Science for Life Laboratory, Stockholm University, 17121 Solna, Sweden
Ingegerd Fransson - Department of Biosciences and Nutrition, Karolinska Institutet, and Center for Biotechnology, 14183 Huddinge, Sweden
Hannele K Koillinen - Department of Clinical Genetics, Helsinki University Hospital, 00029 Helsinki, Finland
Jorma Rautio - Cleft Palate and Craniofacial Center, Department of Plastic Surgery, Helsinki University Hospital, 00029 Helsinki, Finland
Marie Pegelow - Department of Orthodontics, Stockholm Craniofacial Team, Institute of Odontology, Karolinska Institutet, 17177 Stockholm, Sweden
Agneta Karsten - Department of Orthodontics, Stockholm Craniofacial Team, Institute of Odontology, Karolinska Institutet, 17177 Stockholm, Sweden
Lina Basel-Vanagaite - 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
William Gordon - Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA
Bogi Andersen - Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA
Thomas Svensson - Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, 17121 Solna, Sweden
Jeffrey C Murray - Department of Pediatrics and Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
Robert A Cornell - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Juha Kere - 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
Brian C Schutte - Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.94(1), pp.23-32
DOI: 10.1016/j.ajhg.2013.11.009
PMID: 24360809
PMCID: PMC3882735
NLM abbreviation: Am J Hum Genet
ISSN: 0002-9297
eISSN: 1537-6605
Publisher: United States
Grant note: F31DE022696 / NIDCR NIH HHS T32 HD060555 / NICHD NIH HHS T32 GM008629 / NIGMS NIH HHS AR44882 / NIAMS NIH HHS F31 DE022696 / NIDCR NIH HHS R01 DE021071 / NIDCR NIH HHS R01 AR044882 / NIAMS NIH HHS R01 DE008559 / NIDCR NIH HHS DE13513 / NIDCR NIH HHS R01 DE013513 / NIDCR NIH HHS R01 DE023575 / NIDCR NIH HHS GM008629 / NIGMS NIH HHS R03 AR061586 / NIAMS NIH HHS DE021071 / NIDCR NIH HHS AR061586 / NIAMS NIH HHS R37 DE008559 / NIDCR NIH HHS DE08559 / NIDCR NIH HHS U01 DE020057 / NIDCR NIH HHS
Language: English
Date published: 01/02/2014
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025470602771

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