Mutations in NOTCH1 cause aortic valve disease

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Abstract
A genetic basis for aortic valve calcification, a leading cause of heart disease in adults, has been discovered in a study of congenital heart disease in five generations of the same family. The disease was apparent in family members with a mutation in the transcriptional regulator NOTCH1. The mutant gene causes heart valve defects in transgenic mice. NOTCH1 mutations have previously been identified in human blood cancers, but this is the first indication that it has a role in the development of the heart. Calcification of the aortic valve is the third leading cause of heart disease in adults1. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1–2% of the population2. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.