NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling

McBride, Kim L.; Riley, Maurisa F.; Zender, Gloria; Fitzgerald-Butt, Sara; Towbin, Jeffrey A.; Belmont, John W.; Cole, Susan E.

doi:10.1093/hmg/ddn187

Cited by 182 publications

(186 citation statements)

References 29 publications

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“…The most common malformation associated with CoA is BAov. Autopsy examinations showed 54%-85% of patients with CoA have a BAov [13]. The coexistence of BAov and CoA is important to consider, because it places the patient at a higher risk of aortic complications.…”

Section: Associated Cardiac and Extracardiac Lesionsmentioning

confidence: 99%

Late Coarctation Presenters Suffer Chronic Hypertension Resisting to Medicine Treatment

Petropoulos

Moschovi

Khudiyeva³

et al. 2018

Journal of Clinic Sciences

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Coarctation of the aorta (CoA) is a common Congenital Heart Disease (CHD) presenting with many symptoms and signs, in any age group. From its dramatic appearance as a part of Hypo plastic Left Heart Syndrome (HLHS), to early Congestive Heart Failure(CHF)in neonatal and early infantile age, to undetected Hypertension (HTN) in early or even late adulthood. The aim of this short review is to present this unique CHD, underline the presentation of late detected CoA, presenting with HTN and its impact in treating resistant HTN even after successful surgical treatment. Finally, the late onset HTN, following successful surgical treatment and its medicine management will be addressed. This difficult to control on mono or dual pharmacotherapy and the late complications of persistent uncontrolled HTN is the basic reason that these patients are a long-life follow-up population with important medical needs and increasing morbidity and mortality. Abriviations

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Section: Associated Cardiac and Extracardiac Lesionsmentioning

confidence: 99%

Late Coarctation Presenters Suffer Chronic Hypertension Resisting to Medicine Treatment

Petropoulos

Moschovi

Khudiyeva³

et al. 2018

Journal of Clinic Sciences

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“…Furthermore, mutations in NOTCH2 and the Notch ligand JAGGED1 are responsible for Alagille syndrome, which is characterized by pulmonary stenosis, ventricular septal defects, coarctation of the aorta, and tetralogy of Fallot, among other developmental defects 16, 17. Notch1 is expressed in the endothelial cells lining the cardiac OFT during development, and mutations in NOTCH1 have been linked primarily to human BAV and other left‐sided cardiac malformations 18, 19. Although these studies indicate the important role for Notch signaling in the development of the cardiac OFT and aortic valve, the underlying mechanisms and the cell lineages in which Notch1 is required have not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

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BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.

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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: 61%

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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NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling

Cited by 182 publications

References 29 publications

Late Coarctation Presenters Suffer Chronic Hypertension Resisting to Medicine Treatment

Late Coarctation Presenters Suffer Chronic Hypertension Resisting to Medicine Treatment

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Notch Signaling in Aortic Valve Development and Disease

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