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

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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.

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Figure 1: Mutations in TGFBR2 cause multiple developmental anomalies.
Figure 2: Mutations in TGFBR1 cause multiple developmental anomalies.
Figure 3: Histology and ultrastructure of the aortic wall.
Figure 4: Assessment of TGFβ signaling in cells and tissues from affected individuals.

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  • 03 February 2005

    The full text and PDF were updated to contain the correct wording of sentence 5 in paragraph 8.


  1. *Note: In the version of this article initially published online, an error appeared in paragraph 8. The paragraph should read, "Some individuals with mutations in TGFBR1 or TGFBR2 have phenotypes that overlap somewhat with MFS, but none met the diagnostic criteria for MFS15. All affected individuals had manifestations in multiple organ systems that are not associated with MFS (Table 2). In these individuals, aneurysms tend to be particularly aggressive and to rupture at an early age (e.g., individuals 4.II-1 and 5.II-1) or be of a size not associated with high risk in MFS16 (e.g., individual 1.II-1). Therefore, from a management perspective, the distinction from MFS is neither ambiguous nor unimportant. Comprehensive mutation analysis of fibrillin-1 in 93 consecutive individuals referred with classic MFS identified 86 mutations17. We sequenced TGFBR1 and TGFBR2 in the other seven individuals and found no mutations (data not shown)." This mistake has been corrected for the HTML and print versions of the article.


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We thank the families for their interest and cooperation; S. Kahler, C. Scott and H. Collmann for referring affected individuals; M. Awad for assistance in preparing the figures; and D. Devos and J. Bauer for radiological support. This work was supported by the National Marfan Foundation, the William Smilow Center for Marfan Syndrome Research, the Howard Hughes Medical Institute, the Robert Wood Johnson Foundation, the Dana and Albert Broccoli Center for Aortic Diseases, the Bijzonder Onderzoeksfonds of Ghent University, the Institute for the Promotion of Innovation by Science and Technology in Flanders, the National Institutes of Health and the Fund for Scientific Research-Flanders.

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Correspondence to Harry C Dietz.

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Supplementary information

Supplementary Fig. 1

Sequencing of 9 subcloned RT-PCR amplicons from individual 5.II-1 that span the exon 1-2 junction in TGFBR2 mRNA revealed altered splicing in 4. (PDF 43 kb)

Supplementary Note (PDF 180 kb)

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Loeys, B., Chen, J., Neptune, E. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37, 275–281 (2005).

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