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Eur J Hum Genet. 2019 Feb 26. doi: 10.1038/s41431-019-0357-x. [Epub ahead of print]

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

Author information

1
Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA.
2
Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
3
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, USA.
4
Department of Cardiovascular Surgery, Texas Heart Institute, Houston, USA.
5
Department of Cardiothoracic Vascular Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA.
6
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
7
Center for Medical Genetics, Department of Cardiology, Ghent University Hospital, Ghent, Belgium.
8
Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA. Dianna.M.Milewicz@uth.tmc.edu.

Abstract

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.

PMID:
30809044
DOI:
10.1038/s41431-019-0357-x

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