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

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

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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.

Original languageEnglish (US)
Pages (from-to)2886-2893
Number of pages8
JournalHuman molecular genetics
Volume17
Issue number18
DOIs
StatePublished - Sep 8 2008

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Hypoplastic Left Heart Syndrome
Aortic Coarctation
Aortic Valve Stenosis
Ligands
Mutation
Endothelium
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mcbride, K. L., Riley, M. F., Zender, G. A., Fitzgerald-Butt, S. M., Towbin, J., Belmont, J. W., & Cole, S. E. (2008). NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Human molecular genetics, 17(18), 2886-2893. https://doi.org/10.1093/hmg/ddn187

NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. / Mcbride, Kim L.; Riley, Maurisa F.; Zender, Gloria A.; Fitzgerald-Butt, Sara M.; Towbin, Jeffrey; Belmont, John W.; Cole, Susan E.

In: Human molecular genetics, Vol. 17, No. 18, 08.09.2008, p. 2886-2893.

Research output: Contribution to journalArticle

Mcbride, KL, Riley, MF, Zender, GA, Fitzgerald-Butt, SM, Towbin, J, Belmont, JW & Cole, SE 2008, 'NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling', Human molecular genetics, vol. 17, no. 18, pp. 2886-2893. https://doi.org/10.1093/hmg/ddn187
Mcbride, Kim L. ; Riley, Maurisa F. ; Zender, Gloria A. ; Fitzgerald-Butt, Sara M. ; Towbin, Jeffrey ; Belmont, John W. ; Cole, Susan E. / NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. In: Human molecular genetics. 2008 ; Vol. 17, No. 18. pp. 2886-2893.
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