Journal Article

Mutations in NOTCH1 cause aortic valve disease

Barnes, Robert, Garg, Vidu, Muth, Alecia N., Grossfeld, Paul D., Schluterman, Marie K., King, Isabelle N., Ransom, Joshua F., Srivastava, Deepak

2005

Overview

NOTCH1 in heart disease 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 adults 1 . The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1–2% of the population 2 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adult / Animals / Aortic Valve - abnormalities / Aortic Valve - pathology / Base Sequence / Biological and medical sciences / Calcinosis - genetics / Calcium / Cardiology. Vascular system / Cardiovascular disease / Cardiovascular diseases / Child / Chromosomes, Human, Pair 9 - genetics / Core Binding Factor Alpha 1 Subunit / COS Cells / DNA Mutational Analysis / Endocardial and cardiac valvular diseases / Female / Gene Expression Regulation, Developmental / Genotype & phenotype / Heart / Heart Valve Diseases - congenital / Heart Valve Diseases - genetics / Heart Valve Diseases - pathology / Heart Valve Diseases - physiopathology / Humanities and Social Sciences / Humans / In Situ Hybridization / letter / Lod Score / Male / Medical sciences / Mice / multidisciplinary / Mutation / Mutation - genetics / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Pedigree / Phenotype / Receptor, Notch1 / Receptors, Cell Surface - chemistry / Receptors, Cell Surface - genetics / Receptors, Cell Surface - metabolism / Repressor Proteins - genetics / Repressor Proteins - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Transcription Factors - chemistry / Transcription Factors - genetics / Transcription Factors - metabolism