Boileau, C. et al. (2012) TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nature Genetics, 44(8), pp. 916-921. (doi: 10.1038/ng.2348)
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Abstract
A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.
| Item Type: | Articles (Letter) |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Padmanabhan, Professor Sandosh |
| Authors: | Boileau, C., Guo, D.-C., Hanna, N., Regalado, E. S., Detaint, D., Gong, L., Varret, M., Prakash, S. K., Li, A. H., d'Indy, H., Braverman, A. C., Grandchamp, B., Kwartler, C. S., Gouya, L., Santos-Cortez, R. L. P., Abifadel, M., Leal, S. M., Muti, C., Shendure, J., Gross, M.-S., Rieder, M. J., Vahanian, A., Nickerson, D. A., Michel, J. B., Jondeau, G., Milewicz, D. M., and Padmanabhan, S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Nature Genetics |
| Publisher: | Nature Publishing Group |
| ISSN: | 1061-4036 |
| ISSN (Online): | 1546-1718 |
| Related URLs: |
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