Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms

McKellar, Stephen H.; Tester, David J.; Yagubyan, Marineh; Majumdar, Ramanath; Ackerman, Michael J.; Sundt, Thoralf M.

doi:10.1016/j.jtcvs.2007.02.041

Cited by 249 publications

(180 citation statements)

References 24 publications

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“…Such an EMT defect is rescued by exogenous Fgf8, suggesting that Notch functions through Fgf8 to activate EMT of OFT cushions (High et al, 2009). NOTCH1 mutations are observed in some families with a multi-generation history of BAV and/or calcific aortic stenosis (Garg et al, 2005;Garg, 2006;McKellar et al, 2007;McBride et al, 2008;Rusanescu et al, 2008). Because Notch1 is capable of suppressing Runx2, which promotes calcification (Garg et al, 2005), NOTCH1 mutations in humans might cause RUNX2 upregulation with consequent valve calcification.…”

Section: Notch Signalingmentioning

confidence: 99%

Partitioning the heart: mechanisms of cardiac septation and valve development

et al. 2012

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Heart malformations are common congenital defects in humans. Many congenital heart defects involve anomalies in cardiac septation or valve development, and understanding the developmental mechanisms that underlie the formation of cardiac septal and valvular tissues thus has important implications for the diagnosis, prevention and treatment of congenital heart disease. The development of heart septa and valves involves multiple types of progenitor cells that arise either within or outside the heart. Here, we review the morphogenetic events and genetic networks that regulate spatiotemporal interactions between the cells that give rise to septal and valvular tissues and hence partition the heart.

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Section: Notch Signalingmentioning

confidence: 99%

Partitioning the heart: mechanisms of cardiac septation and valve development

et al. 2012

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“…It should be noted that NOTCH1 mutations can also cause an array of isolated cardiovascular defects, including aortic valve defects, hypoplastic left heart syndrome and tetralogy of Fallot (Garg et al, 2005;Kerstjens-Frederikse et al, 2016;McBride et al, 2008;McKellar et al, 2007;Mohamed et al, 2006). Such mutations include missense, nonsense and truncation mutations, implying that heterozygous loss of NOTCH1 function can lead to either AdamsOliver syndrome (Fig.…”

Section: Introductionmentioning

confidence: 99%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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“…In a smaller unrelated family, a NOTCH1 frameshift mutation segregated with a similar aortic valve phenotype. Observations of missense NOTCH1 mutations in a subset (~5 %) of individuals with BAV have also been reported with supporting functional data indicating impaired Notch signaling [7,8]. These publications suggested that NOTCH1 haploinsufficiency was a cause of BAV in humans.…”

Section: Notch1 Mutations and Aortic Valve Diseasementioning

confidence: 62%

Notch Signaling in Aortic Valve Development and Disease

Garg

2016

Etiology and Morphogenesis of Congenital Heart Disease

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Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1 % in the population. BAV results in significant morbidity usually during adulthood due to its association with aortic valve calcification and ascending aortic aneurysms. Mutations in the signaling and transcriptional regulator, NOTCH1, are a cause of bicuspid aortic valve in non-syndromic autosomal dominant human pedigrees. The Notch signaling pathway is critical for multiple cellular processes during both development and disease and is expressed in the developing and adult aortic valve consistent with the cardiac phenotypes identified in affected family members. Recent work has begun to elucidate the molecular mechanisms underlying the link between Notch1 signaling and the development of BAV and valve calcification. Using in vitro approaches, loss of Notch signaling has been shown to contribute to aortic valve calcification via Runx2-, Sox9-, and Bmp2-dependent mechanisms. In addition, Notch1 signaling has been shown to be responsive to nitric oxide signaling during this disease process. A new highly penetrant mouse model of aortic valve disease using Notch1 haploinsufficient mice that are backcrossed in an endothelial nitric oxide synthase (Nos3)-null background was generated. Notch1 and Nos3 compound mutant mice (Notch1 þ/-;Nos3 -/-) display a nearly 100 % incidence of aortic valve malformations, most commonly BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. Based upon the initial discovery of NOTCH1 mutations in

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Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms

Cited by 249 publications

References 24 publications

Partitioning the heart: mechanisms of cardiac septation and valve development

Partitioning the heart: mechanisms of cardiac septation and valve development

The developmental biology of genetic Notch disorders

Notch Signaling in Aortic Valve Development and Disease

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