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Letter
Nature Genetics  32, 285 - 289 (2002)
Published online: 3 September 2002; | doi:10.1038/ng985

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes

Shinji Kondo1, 19, Brian C. Schutte1, 2, 19, Rebecca J. Richardson3, 20, Bryan C. Bjork4, 20, Alexandra S. Knight3, Yoriko Watanabe1, Emma Howard3, Renata L.L. Ferreira de Lima5, Sandra Daack-Hirsch1, Achim Sander6, 21, Donna M. McDonald-McGinn7, Elaine H. Zackai7, Edward J. Lammer8, Arthur S. Aylsworth9, Holly H. Ardinger10, Andrew C. Lidral11, Barbara R. Pober12, Lina Moreno13, Mauricio Arcos-Burgos14, Consuelo Valencia14, Claude Houdayer15, Michel Bahuau15, 16, Danilo Moretti-Ferreira5, Antonio Richieri-Costa17, Michael J. Dixon3 & Jeffrey C. Murray1, 2, 18

1  Department of Pediatrics, The University of Iowa, Iowa City, Iowa 52242, USA.

2  Interdisciplinary PhD Program in Genetics, The University of Iowa, Iowa City, Iowa 52242, USA.

3  School of Biological Sciences and Department of Dental Medicine and Surgery, University of Manchester, Oxford Road, Manchester, UK.

4  Harvard University, Brigham and Women's Hospital, Boston, Massachusetts, USA.

5  Servico de Aconselhamento, Genetico da Universidade Estadual Paulista, Botucatu S.P., Brazil.

6  Clinic of Oral-Maxillofacial Surgery, University of Hamburg, Hamburg, Germany.

7  Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

8  Medical Genetics, Children's Hospital, Oakland, California, USA.

9  Department of Pediatrics and Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

10  Department of Pediatrics, University of Kansas, Children's Medical Center, Kansas City, Kansas, USA.

11  Department of Orthodontics, The University of Iowa, Iowa City, Iowa, USA.

12  Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

13  PhD Program in Oral Sciences, The University of Iowa, Iowa City, Iowa, USA.

14  Universidad de Antioquia, Medellin, Colombia.

15  Service de Biochimie et Biologie Moléculaire, Hôpital d'Enfants Armand-Trousseau, Paris, France.

16  Service de Chirurgie Maxillofaciale et Plastique, Stomatologie, Hôpital d'Enfants Armand-Trousseau, Paris, France.

17  Departmento de Genetica Clinica, Hospital de Pesquisa e Reabilitacao de Lesoes Labio-Palatais, Universidade de São Paulo, Bauru, Brazil.

18  Department of Biology, The University of Iowa, Iowa City, Iowa 52242, USA.

19  These two authors contributed equally to this work.

20  These two authors contributed equally to this work.

21  Deceased.

Correspondence should be addressed to Jeffrey C. Murray jeff-murray@uiowa.edu
Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix−turn−helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection1, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32−q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits4, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies5. Phenotypic overlap6 and linkage data7 suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.


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European Journal of Human Genetics Original Article (15 Oct 2001)

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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