Human Molecular Genetics Advance Access originally published online on June 30, 2008
Human Molecular Genetics 2008 17(18):2886-2893; doi:10.1093/hmg/ddn187
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NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling
1 Center for Molecular and Human Genetics, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA 2 Department of Pediatrics, College of Medicine 3 Department of Molecular Genetics, Ohio State University, Columbus, OH, USA 4 Department of Pediatrics, Section of Cardiology 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
* To whom correspondence should be addressed at: The Research Institute at Nationwide Children’s Hospital, 700 Children's Dr, Columbus, OH 43209, USA. Tel: +1 6147225484; Fax: +1 6147222817; Email: kim.mcbride{at}nationwidechildrens.org
Received April 2, 2008; Accepted June 27, 2008
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.