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

Autor: Duan XY; Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA., Guo DC; Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA., Regalado ES; Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA., Shen H; Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA.; Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai, China., Coselli JS; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, USA.; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, USA., Estrera AL; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, USA., Safi HJ; Department of Cardiothoracic Vascular Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA., Bamshad MJ; Department of Genome Sciences, University of Washington, Seattle, WA, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA, USA., LeMaire SA; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, USA.; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, USA., De Backer J; Center for Medical Genetics, Department of Cardiology, Ghent University Hospital, Ghent, Belgium., Milewicz DM; Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA. Dianna.M.Milewicz@uth.tmc.edu.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2019 Jul; Vol. 27 (7), pp. 1054-1060. Date of Electronic Publication: 2019 Feb 26.
DOI: 10.1038/s41431-019-0357-x
Abstrakt: 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.
Databáze: MEDLINE
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