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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $99.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Howard DP, Banerjee A, Fairhead JF, Perkins J, Silver LE, Rothwell PM. Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study. Circulation. 2013;127:2031–7.
Prakash SK, Haden-Pinneri K, Milewicz DM. Susceptibility to acute thoracic aortic dissections in patients dying outside the hospital: an autopsy study. Am Heart J. 2011;162:474–9.
Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Jr. et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010;121:e266–369.
Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004;36:855–60.
Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98.
Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012;44:916–21.
van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6.
Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011;109:680–6.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Andrabi S, Bekheirnia MR, Robbins-Furman P, Lewis RA, Prior TW, Potocki L. SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am J Med Genet A. 2011;155A:1165–9.
Teekakirikul P, Milewicz DM, Miller DT, Lacro RV, Regalado ES, Rosales AM, et al. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. Am J Med Genet A. 2013;161:185–91.
Heald B, Rigelsky C, Moran R, LaGuardia L, O'Malley M, Burke CA, et al. Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4. Am J Med Genet A. 2015;167A:1758–62.
Guo DC, Regalado ES, Gong L, Duan X, Santos-Cortez RL, Arnaud P, et al. LOX mutations predispose to thoracic aortic aneurysms and dissections. Circ Res. 2016;118:928–34.
Renard M, Francis C, Ghosh R, Scott AF, Witmer PD, Ades LC, et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol. 2018;72:605–15.
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.
Guo DC, Hostetler EM, Fan Y, Kulmacz RJ, Zhang D, Nickerson DA, et al. Heritable thoracic aortic disease genes in sporadic aortic dissection. J Am Coll Cardiol. 2017;70:2728–30.
Liang M, Liang YY, Wrighton K, Ungermannova D, Wang XP, Brunicardi FC, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol Cell Biol. 2004;24:7524–37.
Xu J, Attisano L. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA. 2000;97:4820–5.
Guo DC, Duan XY, Regalado ES, Mellor-Crummey L, Kwartler CS, Kim D, et al. Loss-of-function mutations in YY1AP1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. Am J Hum Genet. 2017;100:21–30.
Mao X, Debenedittis P, Sun Y, Chen J, Yuan K, Jiao K, et al. Vascular smooth muscle cell Smad4 gene is important for mouse vascular development. Arterioscler Thromb Vasc Biol. 2012;32:2171–7.
Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2011;44:85–8.
Carr JC, Dahdaleh FS, Wang D, Howe JR. Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling. J Surg Res. 2012;174:211–4.
This work is supported by National Heart, Lung and Blood Institute (RO1 HL109942) and the John Ritter Foundation to Dr. Milewicz, National Human Genome Research Institute (1U54HG006493) to Drs. Nickerson and Bamshad.