title: NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.
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.
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Maurisa F
authors.initials: MF
authors.lastname: Riley
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Zender
authors.forename: Sara M
authors.initials: SM
authors.lastname: Fitzgerald-Butt
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.forename: Susan E
authors.initials: SE
authors.lastname: Cole
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006352:Heart Ventricles / Q000002:abnormalities* / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014694:Ventricular Outflow Obstruction / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology*; D044465:White People / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins