<i>SMAD4</i> mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction

Andrabi, Sara; Bekheirnia, Mir Reza; Robbins-Furman, Patricia; Lewis, Richard A.; Prior, Thomas W.; Potocki, Lorraine

doi:10.1002/ajmg.a.33968

Cited by 65 publications

(65 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The symptoms of HHT include epistaxis, telangiectases, and arteriovenous malformations, which are most often found in the lungs, brain, liver and gastrointestinal tract. In addition, SMAD4 mutations have been identified in families with juvenile polyposis, aortophathy, and mitral valve dysfunction (Andrabi et al, 2011 humans with IRF6 mutation, whereas Irf6 +/R84C mice do not show digit developmental defects. These results suggest that a compromised SMAD-dependent, TGFβ-mediated IRF6 signaling cascade might be responsible for developmental defects associated with PPS.…”

Section: Discussionmentioning

confidence: 99%

Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice

et al. 2013

View full text Add to dashboard Cite

SUMMARYCleft palate is one of the most common human birth defects and is associated with multiple genetic and environmental risk factors. Although mutations in the genes encoding transforming growth factor beta (TGFβ) signaling molecules and interferon regulatory factor 6 (Irf6) have been identified as genetic risk factors for cleft palate, little is known about the relationship between TGFβ signaling and IRF6 activity during palate formation. Here, we show that TGFβ signaling regulates expression of Irf6 and the fate of the medial edge epithelium (MEE) during palatal fusion in mice. Haploinsufficiency of Irf6 in mice with basal epithelial-specific deletion of the TGFβ signaling mediator Smad4 (Smad4

show abstract

Section: Discussionmentioning

confidence: 99%

Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice

et al. 2013

View full text Add to dashboard Cite

show abstract

“…To explain how mutation of TGF-β signal-related molecules, especially in inflammatory cells, leads to damage or remodeling of the vascular system, we can use the mechanism of hereditary hemorrhagic telangiectasia (HHT). HHT is caused by mutations of several TGF-β signal-related molecules, including ALK1, endoglin, and Smad4 (49,50), and mutation of Smad4, an obligate partner of Smad3, could induce the dilation of aorta (49). At the early stage of HHT development, lymphocytes, includ-and TGF-β (10 ng/ml) (R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency

Chen²,

et al. 2013

J. Clin. Invest.

View full text Add to dashboard Cite

Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3 -/-mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4 + T cells from Smad3 -/-mice also induced aortitis in Smad3 +/+ recipient mice, while depletion of CD4 + T cells in Smad3 -/-mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-γ deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3 +/-mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3 -/-CD4 + T cells secreted more GM-CSF than Smad3 +/+ CD4 + T cells. GM-CSF induced CD11b + Gr-1 + Ly-6C hi inflammatory monocyte accumulation in the aortic root, but administration of anti-GM-CSF mAb to Smad3 -/-mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.

show abstract

“…Similarly, SMAD4 was recently implicated in human aortic disease. A pedigree was described with the combination of juvenile polyposis, aortopathy, and mitral valve disease (Andrabi et al 2011). Aortic aneurysm with pathologic evidence of cystic medial necrosis was noted in aortic tissue from a mutation carrier.…”

Section: Canonical (Smad) and Noncanonical (Mapk) Tgf-b Signalingmentioning

confidence: 99%

“…þ/2 mice ) as well as aortopathy in humans caused by loss of function mutations in SMAD3 and SMAD4 (van de Laar et al 2010;Andrabi et al 2011). It could also help explain the skewed mutational repertoire in TGF-b receptor mutations (LDS) favoring intact receptor complexes unable to transduce canonical signaling .…”

Section: Canonical (Smad) and Noncanonical (Mapk) Tgf-b Signalingmentioning

confidence: 99%

The Genetic Basis of Aortic Aneurysm

Lindsay

Dietz

2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

Gene identification in human aortic aneurysm conditions is proceeding at a rapid pace and the integration of pathogenesis-based management strategies in clinical practice is an emerging reality. Human genetic alterations causing aneurysm involve diverse gene products including constituents of the extracellular matrix, cell surface receptors, intracellular signaling molecules, and elements of the contractile cytoskeleton. Animal modeling experiments and human genetic discoveries have extensively implicated the transforming growth factor-b (TGF-b) cytokine-signaling cascade in aneurysm progression, but mechanistic links between many gene products remain obscure. This chapter will integrate human genetic alterations associated with aortic aneurysm with current basic research findings in an attempt to form a reconciling if not unifying model for hereditary aortic aneurysm.A mong the myriad blood vessels within the body, the large capacitance arteries adjacent to the heart are unique in structure, function, and in their capacity for derangement in disease states. The clear enrichment of involvement of the proximal ascending thoracic aorta, and more specifically the sinuses of Valsalva, in inherited forms of thoracic aortic aneurysm (TAA) has been historically attributed to the unique functional demands and hemodynamic environment of this aortic segment. The aorta is a relatively unique organ in that its critical functional components are located in the extracellular space, whereas the cellular components of the aorta may act primarily to support the development and homeostasis of the supporting matrix. Cardiovascular surgeons show this interesting biology in common surgical practice. Large aortic segments are routinely replaced entirely with synthetic materials such as Dacron, demonstrating the dispensability of aortic cellular components for minimal critical function (to serve as a conduit and distribution network for blood flow). Despite its seemingly simple nature, the aorta has evolved into a complex organ with spatial variation in structure. During cardiac systole, the proximal ascending aorta has the ability to accept pressure and volume loads (capacitance) and to transmit them distally during diastole through recoil (elastance) with the least loss of energy. These requirements are reflected by variation in the major compoEditors:

show abstract

SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction

Cited by 65 publications

References 22 publications

Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice

Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice

GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency

The Genetic Basis of Aortic Aneurysm

Contact Info

Product

Resources

About