Genetic Insights Into Bicuspid Aortic Valve Disease

Debiec, Radoslaw; Sall, Hanish; Samani, Nilesh J.; Bolger, Aidan P.

doi:10.1097/crd.0000000000000147

Cited by 10 publications

(8 citation statements)

References 65 publications

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“…We screened 20 genes known to be associated with BAV (Debiec et al, ). In SMAD6 , a novel in‐frame variant (c.1168_1173dup; p.Gly390_Ile391dup) was identified.…”

Section: Resultsmentioning

confidence: 99%

“…The called variants were filtered and prioritized using a four‐step strategy. Initially, we screened 20 genes known to be associated with BAV ( NOTCH1, MAT2A, TGFBR2, ARHGAP31, MATR3, NKX2.5, MAML1, JARID2, ENG, ACTA2, MYH6, MYH7, FBN1, SMAD6, AXIN1, PDIA2, KCNJ2, SMARCA4, JAG1, and GATA5 ) (Debiec, Sall, Samani, & Bolger, ). Next step, we removed variants below 10× coverage.…”

Section: Methodsmentioning

confidence: 99%

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A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

Park

Jang

et al. 2019

Molec Gen & Gen Med

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Background Bicuspid aortic valve (BAV) is the most common congenital heart defect with a prevalence of 1%–2% in the general population. NOTCH1 , SMAD6 , and GATA5 are associated with BAV in humans, but few cases have been reported that did not involve NOTCH1 . Here, we identified novel in‐frame variants in SMAD6 (c.1168_1173dup; p.Gly390_Ile391dup) in a BAV patient, who presented with dilatation of the ascending aorta and severe calcification of the aortic valve. Methods Twenty BAV associated genes were screened by exome sequencing. Functional effects of SMAD6 variant were investigated using bone morphogenetic protein (BMP) signaling assays through in vitro functional study. Results Exome sequencing revealed he had novel in‐frame variants in the SMAD6 gene (c.1168_1173dup; p.Gly390_Ile391dup). SMAD6 is known to be an inhibitory protein in the BMP signaling pathway. In vitro functional study of the p.Gly390_Ile391dup variant revealed impaired inhibition of BMP signaling and BMP‐induced alkaline phosphatase activity. Conclusion In conclusion, we identified a novel SMAD6 variant causing a severely calcified BAV and TAA, which contributes to our understanding of the clinical and genetic background of SMAD6 ‐related BAV.

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“…We screened 20 genes known to be associated with BAV (Debiec et al, ). In SMAD6 , a novel in‐frame variant (c.1168_1173dup; p.Gly390_Ile391dup) was identified.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

Park

Jang

et al. 2019

Molec Gen & Gen Med

View full text Add to dashboard Cite

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“…Bicuspid aortic valve (BAV) is the most common congenital heart disease, with an estimated prevalence of 0.4–2.25% [ 32 ]. Abnormal aortic cusp formation during development leads to two abnormal, rather than three normal, aortic cusps.…”

Section: Genetically Triggered Thoracic Aortic Aneurysmsmentioning

confidence: 99%

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms

Malecki

Hambly

Jeremy

et al. 2020

IJMS

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Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.

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“…While a normal aortic valve consists of three leaflets (tricuspid aortic valve, TAV), a BAV has only two free moveable/floating leaflets either with or without a raphe. BAV can occur sporadically or can be inherited, and mutations in e.g., NOTCH1 , TGFBR1 and SMAD6 , have been reported to be associated with BAV [1,2]. Furthermore, there is a remarkable male preponderance of 3:1 in the total population.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Colony Forming Cells as an Autologous Model to Study Endothelial Dysfunction in Patients with a Bicuspid Aortic Valve

Pol

Bons

Lodder

et al. 2019

IJMS

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Bicuspid aortic valve (BAV), the most common congenital heart defect, is associated with an increased prevalence of aortic dilation, aortic rupture and aortic valve calcification. Endothelial cells (ECs) play a major role in vessel wall integrity. Little is known regarding EC function in BAV patients due to lack of patient derived primary ECs. Endothelial colony forming cells (ECFCs) have been reported to be a valid surrogate model for several cardiovascular pathologies, thereby facilitating an in vitro system to assess patient-specific endothelial dysfunction. Therefore, the aim of this study was to investigate cellular functions in ECFCs isolated from BAV patients. Outgrowth and proliferation of ECFCs from patients with BAV (n = 34) and controls with a tricuspid aortic valve (TAV, n = 10) were determined and related to patient characteristics. Interestingly, we were only able to generate ECFCs from TAV and BAV patients without aortic dilation, and failed to isolate ECFC colonies from patients with a dilated aorta. Analyzing EC function showed that while proliferation, cell size and endothelial-to-mesenchymal transition were similar in TAV and BAV ECFCs, migration and the wound healing capacity of BAV ECFCs is significantly higher compared to TAV ECFCs. Furthermore, calcification is blunted in BAV compared to TAV ECFCs. Our results reveal ECs dysfunction in BAV patients and future research is required to unravel the underlying mechanisms and to further validate ECFCs as a patient-specific in vitro model for BAV.

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Genetic Insights Into Bicuspid Aortic Valve Disease

Cited by 10 publications

References 65 publications

A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms

Endothelial Colony Forming Cells as an Autologous Model to Study Endothelial Dysfunction in Patients with a Bicuspid Aortic Valve

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