Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.

Autor: Cox TC; Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.; Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington.; Department of Oral & Craniofacial Science, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri., Lidral AC; Lidral Orthodontics, Rockford, Michigan., McCoy JC; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio., Liu H; Department of Anatomy and Cell Biology and Anatomy, University of Iowa, Iowa City, Iowa., Cox LL; Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.; Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington.; Department of Oral & Craniofacial Science, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri.; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington., Zhu Y; New South Wales Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.; Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia., Anderson RD; Department of Oral & Craniofacial Science, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri., Moreno Uribe LM; Department of Orthodontics & the Iowa Institute for Oral Health Research, University of Iowa, Iowa City, Iowa., Anand D; Department of Biological Sciences, University of Delaware, Newark, Delaware., Deng M; Birth Defects Research Laboratory, University of Washington, Seattle, Washington., Richter CT; Department of Orthodontics & the Iowa Institute for Oral Health Research, University of Iowa, Iowa City, Iowa., Nidey NL; Department of Pediatrics, University of Iowa, Iowa City, Iowa., Standley JM; Department of Pediatrics, University of Iowa, Iowa City, Iowa., Blue EE; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington., Chong JX; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington., Smith JD; Department of Genome Sciences, University of Washington, Seattle, Washington., Kirk EP; New South Wales Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.; Centre for Clinical Genetics, Sydney Children's Hospital, New South Wales, Australia., Venselaar H; Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, Nijmegen, The Netherlands., Krahn KN; UVA Center for Advanced Medical Analytics, School of Medicine, University of Virginia, Charlottesville, Virginia., van Bokhoven H; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Zhou H; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.; Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands., Cornell RA; Department of Anatomy and Cell Biology and Anatomy, University of Iowa, Iowa City, Iowa., Glass IA; Birth Defects Research Laboratory, University of Washington, Seattle, Washington.; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington., Bamshad MJ; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.; Department of Genome Sciences, University of Washington, Seattle, Washington., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, Washington., Murray JC; Department of Pediatrics, University of Iowa, Iowa City, Iowa., Lachke SA; Department of Biological Sciences, University of Delaware, Newark, Delaware., Thompson TB; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio., Buckley MF; New South Wales Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia., Roscioli T; New South Wales Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.; Centre for Clinical Genetics, Sydney Children's Hospital, New South Wales, Australia.; Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia.; Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2019 Oct; Vol. 40 (10), pp. 1813-1825. Date of Electronic Publication: 2019 Jun 18.
DOI: 10.1002/humu.23793
Abstrakt: 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.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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