SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections.

TitleSMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections.
Publication TypeJournal Article
Year of Publication2019
AuthorsDuan, X-Y, Guo, D-C, Regalado, ES, Shen, H, Coselli, JS, Estrera, AL, Safi, HJ, Bamshad, MJ, Nickerson, DA, LeMaire, SA, De Backer, J, Milewicz, DM
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalEur J Hum Genet
Date Published2019 Jul

SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c.290G>T, p.(Arg97Leu), not present in population databases and predicted to be damaging to protein function, was identified in a family with thoracic aortic disease and no evidence of HHT or JPS. Cellular studies revealed that the SMAD4 p.(Arg97Leu) alteration increased SMAD4 ubiquitination and 26S proteasome-mediated protein degradation. Smooth muscle cells (SMCs) infected with lentivirus expressing the SMAD4 p.(Arg97Leu) variant demonstrated reduced contractile protein gene expression when compared to that of wild-type SMAD4. In addition, two rare variants were identified in individuals with early age of onset of thoracic aortic dissection. These results suggest that SMAD4 rare missense variants can lead to thoracic aortic disease in individuals who do not have JPS or HHT.

Alternate JournalEur. J. Hum. Genet.
PubMed ID30809044
Grant ListRO1 HL62594 / / National Heart and Lung Institute (NHLI) /
1U54HG006493 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
R01 HL109942 / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States