TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome
Open accessAbstract
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.
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- Authors
- National Heart, L., 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.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Inserm (FR)
- Memorial Hermann (US)
- Washington University in St. Louis (US)
- Assistance Publique – Hôpitaux de Paris (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Baylor College of Medicine (US)
- University of Washington (US)
- Corresponding author
- Milewicz, Dianna M
- ORCID
- Guo, Dong-Chuan
- Hanna, Nadine
- Regalado, Ellen S
- Gong, Limin
- Varret, Mathilde
- Prakash, Siddharth K
- Li, Alexander H
- Braverman, Alan C
- Kwartler, Callie S
- Gouya, Laurent
- Abifadel, Marianne
- Leal, Suzanne M
- Muti, Christine
- Shendure, Jay
- Rieder, Mark J
- Vahanian, Alec
- Nickerson, Deborah A
- Michel, Jean Baptiste
- Jondeau, Guillaume
- Milewicz, Dianna M
- Venue
- Nature Genetics
- Published
- 2012-07-08
- Volume
- 44
- Issue
- 8
- Pages
- 916-921
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4033668
- OpenAlex
- W2025073474
- Cited by
- 382
- References
- 36
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 27 · 2023: 19 · 2022: 28 · 2021: 27 · 2020: 21 · 2019: 20 · 2018: 25 · 2017: 30 · 2016: 34 · 2015: 39 · 2014: 48 · 2013: 26 · 2012: 9
- FWCI
- 23.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Wellcome Trust (090532)
- National Institutes of Health (5p50hl083794-05, 1rc2hl103010-01)
- National Heart, Lung, and Blood Institute (RC2HL102925, R01 HL62594, RC2HL102926, RC2HL102923, R01HL109942, UC2HL102924, P50HL083794-01, RC2HL-103010, UC2HL102925, UC2HL102923, UC2HL103010, RC2HL102924, P50-HL083794, R01HL062594, UC2HL102926)
- National Center for Research Resources (UL1RR024148)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic aneurysm repair treatments
- Keywords
- transforming growth factor-beta2, thoracic aortic aneurysm, acute aortic dissection, Marfan syndrome, familial aortic disease, autosomal dominant inheritance, loss-of-function mutations, haploinsufficiency
- MeSH terms
- Aortic Dissection, Female, Humans, Lod Score, Male, Marfan Syndrome, Mutation, Pedigree, Frameshift Mutation, Aortic Aneurysm, Thoracic, Codon, Nonsense, Genetic Predisposition to Disease, Transforming Growth Factor beta2, Genome-Wide Association Study, Haploinsufficiency, Exome
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