1. Departments of Pediatrics,
2. Molecular Biology and
3. Internal Medicine, and
4. the McDermott Center for Human Growth and Development, 6000 Harry Hines Boulevard, Room NA8.124, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA
5. Children's Medical Center, Dallas, Texas 75235, USA
6. Department of Pediatrics, Division of Cardiology, University of California, San Diego 92123, USA
7. †Present address: Gladstone Institute of Cardiovascular Disease and Department of Pediatrics, University of California, San Francisco, 1650 Owens Street, San Francisco, California 94158, USA

Correspondence to: Vidu Garg^1,5Deepak Srivastava^1,2,4,5,7 Correspondence and requests for materials should be addressed to V.G. (Email: vidu.garg@utsouthwestern.edu) or D.S. (Email: dsrivastava@gladstone.ucsf.edu).

Abstract

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.

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