ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)(1-3) that frequently presents with ascending aortic aneurysm (AscAA)(4). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <= 1% of non-syndromic BAV cases with and without AscAA(5-8), impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

Jaar van publicatie:2019

Trefwoorden:A1 Journal article

BOF-keylabel:ja

BOF-publication weight:10

CSS-citation score:3

Auteurs:International

Authors from:Higher Education

Toegankelijkheid:Closed