NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling
Kim L McBride1, Maurisa F Riley, Gloria A Zender
1Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Insights
Mutations in the NOTCH1 gene are linked to congenital cardiovascular defects like aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome. This suggests a shared molecular pathway in their development.
Area of Science:
- Cardiovascular Development
- Molecular Genetics
- Developmental Biology
Background:
- Congenital cardiovascular malformations involving the left ventricular outflow tract (LVOT), including aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS), share developmental origins.
- The precise etiology of most LVOT defects remains elusive, though a significant genetic influence is recognized.
Purpose of the Study:
- To investigate the role of the NOTCH1 gene and its signaling pathway in the pathogenesis of a spectrum of LVOT defects.
- To identify specific NOTCH1 mutations associated with these congenital heart conditions.
Main Methods:
- Genetic analysis to identify mutations in the NOTCH1 gene across patients with AVS, COA, and HLHS.
- Functional studies to assess the impact of identified mutations on NOTCH1 signaling, including ligand-induced activation and receptor cleavage.
Main Results:
- Mutations in the NOTCH1 gene were identified in individuals with various LVOT defects.
- Two specific mutations were found to impair JAGGED1-induced NOTCH1 signaling.
- One identified mutation disrupts the S1 cleavage of the NOTCH1 receptor within the Golgi apparatus.
Conclusions:
- NOTCH1 signaling levels are critical during cardiovascular development, and alterations can lead to LVOT defects.
- This study establishes a common molecular pathogenetic mechanism for AVS, COA, and HLHS, explaining their familial co-occurrence.
Abstract:
Congenital aortic valve stenosis (AVS), coarctation of the aorta (COA) and hypoplastic left heart syndrome (HLHS) are congenital cardiovascular malformations that all involve the left ventricular outflow tract (LVOT). They are presumably caused by a similar developmental mechanism involving the developing endothelium. The exact etiology for most LVOT malformations is unknown, but a strong genetic component has been established. We demonstrate here that mutations in the gene NOTCH1, coding for a receptor in a developmentally important signaling pathway, are found across the spectrum of LVOT defects. We identify two specific mutations that reduce ligand (JAGGED1) induced NOTCH1 signaling. One of these mutations perturbs the S1 cleavage of the receptor in the Golgi. These findings suggest that the levels of NOTCH1 signaling are tightly regulated during cardiovascular development, and that relatively minor alterations may promote LVOT defects. These results also establish for the first time that AVS, COA and HLHS can share a common pathogenetic mechanism at the molecular level, explaining observations of these defects co-occurring within families.
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