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 Kress & 4 others Paul Coucke, Daniel B. Rifkin, Anne M. De Paepe, Harry C Dietz

Research output: Contribution to journalArticle

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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Connective Tissue Growth Factor
Phenotype
Craniosynostoses
Mutation
Acute-Phase Reaction
Growth Factor Receptors
Cleft Palate
Transforming Growth Factors
Intellectual Disability
Aneurysm
Heart Diseases
Collagen
Alleles
Ligands
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. / Loeys, Bart L.; Chen, Junji; Neptune, Enid; Judge, Daniel P.; Podowski, Megan; Holm, Tammy; Meyers, Jennifer; Leitch, Carmen C.; Katsanis, Nicholas; Sharifi, Neda; Xu, F. Lauren; Myers, Loretha A.; Spevak, Philip J; Cameron, Duke E.; De Backer, Julie; Hellemans, Jan; Chen, Yan; Davis, Elaine C.; Webb, Catherine L.; Kress, Wolfram; Coucke, Paul; Rifkin, Daniel B.; De Paepe, Anne M.; Dietz, Harry C.

In: Nature Genetics, Vol. 37, No. 3, 2005, p. 275-281.

Research output: Contribution to journalArticle

Loeys, BL, Chen, J, Neptune, E, Judge, DP, Podowski, M, Holm, T, Meyers, J, Leitch, CC, Katsanis, N, Sharifi, N, Xu, FL, Myers, LA, Spevak, PJ, Cameron, DE, De Backer, J, Hellemans, J, Chen, Y, Davis, EC, Webb, CL, Kress, W, Coucke, P, Rifkin, DB, De Paepe, AM & Dietz, HC 2005, 'A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2', Nature Genetics, vol. 37, no. 3, pp. 275-281. https://doi.org/10.1038/ng1511
Loeys, Bart L. ; Chen, Junji ; Neptune, Enid ; Judge, Daniel P. ; Podowski, Megan ; Holm, Tammy ; Meyers, Jennifer ; Leitch, Carmen C. ; Katsanis, Nicholas ; Sharifi, Neda ; Xu, F. Lauren ; Myers, Loretha A. ; Spevak, Philip J ; Cameron, Duke E. ; De Backer, Julie ; Hellemans, Jan ; Chen, Yan ; Davis, Elaine C. ; Webb, Catherine L. ; Kress, Wolfram ; Coucke, Paul ; Rifkin, Daniel B. ; De Paepe, Anne M. ; Dietz, Harry C. / A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. In: Nature Genetics. 2005 ; Vol. 37, No. 3. pp. 275-281.
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AU - Podowski, Megan

AU - Holm, Tammy

AU - Meyers, Jennifer

AU - Leitch, Carmen C.

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AU - Sharifi, Neda

AU - Xu, F. Lauren

AU - Myers, Loretha A.

AU - Spevak, Philip J

AU - Cameron, Duke E.

AU - De Backer, Julie

AU - Hellemans, Jan

AU - Chen, Yan

AU - Davis, Elaine C.

AU - Webb, Catherine L.

AU - Kress, Wolfram

AU - Coucke, Paul

AU - Rifkin, Daniel B.

AU - De Paepe, Anne M.

AU - Dietz, Harry C

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