A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2

Bart L. Loeys, Junji Chen, Enid Neptune, Daniel P. Judge, Megan Podowski, Tammy Holm, Jennifer Meyers, Carmen C. Leitch, Nicholas Katsanis, Neda Sharifi, F. Lauren Xu, Loretha A. Myers, Philip J Spevak, Duke E. Cameron, Julie De Backer, Jan Hellemans, Yan Chen, Elaine C. Davis, Catherine L. Webb, Wolfram KressPaul Coucke, Daniel B. Rifkin, Anne M. De Paepe, Harry C Dietz

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Abstract

We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor β 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 TGFβ 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 TGFβ signaling. These data definitively implicate perturbation of TGFβ 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.

Original languageEnglish (US)
Pages (from-to)275-281
Number of pages7
JournalNature Genetics
Volume37
Issue number3
DOIs
StatePublished - 2005

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ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Loeys, B. L., Chen, J., Neptune, E., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., Spevak, P. J., Cameron, D. E., De Backer, J., Hellemans, J., Chen, Y., Davis, E. C., Webb, C. L., ... Dietz, H. C. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics, 37(3), 275-281. https://doi.org/10.1038/ng1511