Nature Genetics
37, 275 - 281 (2005)
Published online: 30 January 2005; Corrected online: 03 February 2005 | doi:10.1038/ng1511
A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2Bart L Loeys1, Junji Chen1, 2, Enid R Neptune3, Daniel P Judge4, Megan Podowski3, Tammy Holm1, Jennifer Meyers1, 2, Carmen C Leitch1, Nicholas Katsanis1, Neda Sharifi1, 2, F Lauren Xu4, Loretha A Myers1, Philip J Spevak5, Duke E Cameron6, Julie De Backer7, Jan Hellemans7, Yan Chen8, Elaine C Davis9, Catherine L Webb10, Wolfram Kress11, Paul Coucke7, Daniel B Rifkin8, Anne M De Paepe7
& Harry C Dietz1, 21
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 2
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 3
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 4
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 5
Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 6
Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 7
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 8
Departments of Cell Biology and Medicine, New York University School of Medicine, New York, New York, USA. 9
Department of Anatomy and Cell Biology, McGill University, Montreal, Canada. 10
Division of Cardiology, Children's Memorial Hospital, Northwestern University School of Medicine, Chicago, Illinois, USA. 11
Institute of Human Genetics, University of Wuerzburg, Wuerzburg, Germany.
Correspondence should be addressed to Harry C Dietz hdietz@jhmi.eduWe report heterozygous mutations in the genes encoding either type I or type II transforming growth factor  receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGF signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGF signaling. These data definitively implicate perturbation of TGF signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
