FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish |
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| Authors: | Ghassibe-Sabbagh Michella Desmyter Laurence Langenberg Tobias Claes Filip Boute Odile Bayet Bénédicte Pellerin Philippe Hermans Karlien Backx Liesbeth Mansilla Maria Adela Imoehl Sandra Nowak Stefanie Ludwig Kerstin U Baluardo Carlotta Ferrian Melissa Mossey Peter A Noethen Markus Dewerchin Mieke François Geneviève Revencu Nicole Vanwijck Romain Hecht Jacqueline Mangold Elisabeth Murray Jeffrey Rubini Michele Vermeesch Joris R Poirel Hélène A Carmeliet Peter Vikkula Miikka |
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| Institution: | 1Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium;2Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;3Vesalius Research Center, Flanders Institute for Biotechnology, 3000 Leuven, Belgium;4Centre de Génétique, Centre Hospitalier Universitaire de Lille, 59037 Lille, France;5Centre Labiopalatin, Service de Chirurgie Plastique, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium;6Service de Chirurgie Plastique et Reconstructive, Centre Hospitalier Universitaire de Lille, 59037 Lille, France;7Center for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;8Department of Pediatrics, University of Iowa, Iowa City, 52242 IA, USA;9Institute of Human Genetics, University of Bonn, 53012 Bonn, Germany;10Department of Genomics, Life and Brain Center, University of Bonn, 53012 Bonn, Germany;11Medical Genetics Unit, Department of Experimental and Diagnostic Medicine, University of Ferrara, 44121 Ferrara, Italy;12Orthodontic Unit, Dental Hospital & School, University of Dundee, Dundee DD1 4HR, Scotland, UK;13Center for Human Genetics, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium;14Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas 77030, USA |
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| Abstract: | Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish. |
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