Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans
Year: 2019
Type: article
Abstract: Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.
Source: Human Mutation
DOI: 10.1002/humu.23793
Authors: Timothy C. Cox, Andrew C. Lidral, Jason C. McCoy, Huan Liu, Liza L. Cox, Ying Zhu, Ryan D. Anderson, Lina M. Moreno Uribe, Deepti Anand, Mei Deng, Chika T. Richter, Nichole L. Nidey, Jennifer M. Standley, Elizabeth E. Blue, Jessica X. Chong, Joshua D. Smith, Edwin P. Kirk, Hanka Venselaar, Katy N. Krahn, Hans Bokhoven, Huiqing Zhou, Robert A. Cornell, Ian A. Glass, Michael J. Bamshad, Deborah A. Nickerson, Jeffrey C. Murray, Salil A. Lachke, Thomas B. Thompson, Michael F. Buckley, Tony Roscioli
Institutions: University of Washington, Seattle Children's Research Institute, University of Missouri–Kansas City, University of Cincinnati, University of Iowa, Fred Hutch Cancer Center, Hunter Genetics, Prince of Wales Hospital, NSW Health Pathology, University of Delaware, University of Iowa Health Care, Sydney Children's Hospital, Radboud University Nijmegen, Radboud University Medical Center, University of Virginia, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences, UNSW Sydney, Neuroscience Research Australia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: March of Dimes Foundation, Cleft Palate Foundation, American Association of Orthodontists Foundation, Ohio State University, University of Iowa, National Institutes of Health, Injury Prevention Research Center, College of Dentistry, Ohio State University, Medical Research Council, National Health and Medical Research Council, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Child Health and Human Development, National Institute of Dental and Craniofacial Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1068064772, G1247003112, G1489242468, G2191464304, A web-based craniofacial disease gene discovery tool, G2323592246, G3012965645, G3179318004, G3262858048, Structure-Function Investigation of DAN-mediated BMP Antagonism, Global Gene Expression Atlas of Craniofacial Development (Research Project), G3568366834, G391838335, G4261463791, FaceBase 2 Coordinating Center, G5413286379, G5520316217, G6472135083, G690541896, G725692007, G7349955655, G7685928703, G7793826167, G8085356564, UW Center for Mendelian Genomics, G9000028633, G9000057055, G9000128347, G9000141846, G9000145211, G9000345790, G964116735
OpenAlex ID: W2950145545