FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

Kuang, Shao Qing; Medina-Martínez, Olga; Guo, Dong; Gong, Limin; Regalado, Ellen S.; Reynolds, Corey; Boileau, Cathérine; Jondeau, Guillaume; Prakash, Siddharth K.; Kwartler, Callie S.; Zhu, Lawrence Yang; Peters, Andrew M.; Duan, Xue Yan; Bamshad, Michael J.; Shendure, Jay; Nickerson, Debbie; Santos‐Cortez, Regie Lyn P.; Dong, Xiurong; Leal, Suzanne M.; Majesky, Mark W.; Swindell, Eric C.; Jamrich, Milan; Milewicz, Dianna M.

doi:10.1172/jci83778

Cited by 88 publications

(57 citation statements)

References 40 publications

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“…These genes are inherited in an autosomal dominant manner and encode proteins with specific functions or components of signaling pathways in aortic smooth muscle cells (SMCs). The causative genes can be grouped into the following categories: structural and regulatory proteins involved in SMC contractile function ( ACTA2 , MYH11 , MYLK , PRKG1 ) 4–7 ; proteins involved in the maintenance of or SMC adhesion to the extracellular matrix ( FBN1 , MFAP5 , LOX ) 8, 9 ; proteins involved in canonical TGF-β signaling ( TGFBR2 , TGFBR1 , SMAD3 , TGFB2, TGFB3 ) 10–15 ; and proteins involved in SMC metabolism ( MAT2A ) or survival ( FOXE3 ) 16, 17 .…”

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confidence: 99%

Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Milewicz

Trybus

Guo

et al. 2017

ATVB

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The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain (RLC) on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased de-phosphorylation of the RLC, and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix (ECM) through focal adhesions, and mutations in the major protein in the ECM, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.

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confidence: 99%

Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Milewicz

Trybus

Guo

et al. 2017

ATVB

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205

172

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“…Inhibition of MMP activity by doxycycline and MMP2 deletion attenuate disease in both Fbn1 C1039G/ + and Fbn1 mgR/mgR mice (81, 103). Aortic dilation was attenuated in Fbn1 C1039G/ + mice and thoracic aortic ruptures were prevented in Foxe3 −/− mice using drugs or genetic ablation to prevent SMC apoptosis (45, 82). Most likely a multidrug regimen targeting various molecular pathways will be required to prevent thoracic aortic aneurysms and aortic dissections in individuals with an underlying genetic predisposition.…”

Section: Resultsmentioning

confidence: 99%

“…FOXE3 mutations also lead to FTAAD, and the molecular pathogenesis was assessed in a mouse model ( Foxe3 −/− mice). These mutant mice had fewer SMCs in the aortic media and increased SMC apoptosis in response to increased biomechanical forces, thus defining an additional molecular alteration leading to FTAAD (45). …”

Section: Heritable Thoracic Aortic Disease Genes: Importance Of Tgf-βmentioning

confidence: 99%

Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models

2017

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Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β over-activity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

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“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Mariscalco

Debiec

Elefteriades

et al. 2018

JAHA

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BackgroundNonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not the current standard of care in NS‐TADs. We sought to determine the incidence of aortic diseases, the predictive accuracy of available screening tests, and the effectiveness of screening programs in relatives of patients affected by NS‐TADs.Methods and ResultsA systematic literature search on PubMed/MEDLINE, Embase, and the Cochrane Library was conducted from inception to the end of December 2017. The search was supplemented with the Online Mendelian Inheritance in Man database. A total of 53 studies were included, and a total of 2696 NS‐TAD relatives were screened. Screening was genetic in 49% of studies, followed by imaging techniques in 11% and a combination of the 2 in 40%. Newly affected individuals were identified in 33%, 24%, and 15% of first‐, second‐, and third‐degree relatives, respectively. Familial NS‐TADs were primarily attributed to single‐gene mutations, expressed in an autosomal dominant pattern with incomplete penetrance. Specific gene mutations were observed in 25% of the screened families. Disease subtype and genetic mutations stratified patients with respect to age of presentation, aneurysmal location, and aortic diameter before dissection. Relatives of patients with sporadic NS‐TADs were also found to be affected. No studies evaluated the predictive accuracy of imaging or genetic screening tests, or the clinical or cost‐effectiveness of an NS‐TAD screening program.ConclusionsFirst‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs.

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FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

Cited by 88 publications

References 40 publications

Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

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