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

European Journal of Human Genetics : EJHG
Xue-Yan DuanDianna M Milewicz

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.

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Citations

Jun 11, 2020·Journal of Clinical Medicine·Virginia AlbiñanaLuisa María Botella
Aug 10, 2019·Current Opinion in Cardiology·Julie De BackerCathérine Boileau
Jan 31, 2021·Genes·Tyler J CreamerElena Gallo MacFarlane
Feb 27, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Brittany O AicherAreck A Ucuzian
Jun 9, 2020·Trends in Molecular Medicine·Aline VerstraetenBart Loeys
Mar 20, 2021·The Journal of Cardiovascular Surgery·Dianna M MilewiczAlana C Cecchi
Oct 27, 2021·European Journal of Clinical Investigation·Karlijn B RomboutsKak Khee Yeung

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Methods Mentioned

BETA
dissections
dissection
exome sequencing
immunoprecipitation
ubiquitination
pull down

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