Molecular genetics of aortic valve disease

Abstract

Bicuspid aortic valve is the most common type of cardiac malformation and predisposes to aortic valve calcification, which is the third leading cause of heart disease in adults. These seemingly temporally disparate diseases have been described as having genetic influences but limited data exist on the precise genetic causes in humans. Several advances in the molecular genetics of aortic valve formation and calcification have recently been identified and are described here. A large family with autosomal-dominant aortic valve disease consisting of bicuspid aortic valve and aortic valve calcification was studied using genome-wide linkage analysis. This led to the identification of a nonsense mutation in NOTCH1 in affected individuals. This finding was supported by the discovery of a NOTCH1 frameshift mutation in an unrelated family with similar aortic valve disease, suggesting that NOTCH1 haploinsufficiency was a genetic cause of aortic valve malformations and calcification. The NOTCH signaling pathway was linked to a molecular pathway for aortic valve calcification, as NOTCH1 was found to repress activation of Runx2 - a transcription factor critical for osteoblast cell fate that is up-regulated in calcified human aortic valves. The recent genetic and biochemical findings provide novel insights into the molecular and genetic basis for aortic valve dysmorphogenesis and calcification. Future studies focusing on the identification of additional disease-causing and susceptibility genes will aid in the development of prevention strategies. Ultimately, it will be the careful dissection of these molecular pathways that will hopefully lead to novel therapeutic options.