Journal Article

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

Wünnemann, Florian, Bennett, Christopher L., Seman-Senderos, Manuel Alejandro, Lino Cardenas, Christian Lacks, Loeys, Bart L., McCallion, Andrew S., Shah, Asad A., Sobreira, Nara, Kumar, Ajay Anand, Eriksson, Per, Mital, Seema, Wessels, Marja, Ling, Hua, Lehsau, Ann-Cathrin, McClymont, Sarah A., Moats, Cassandra R., Gould, Russell A., Björk, Hanna M., Van Laer, Lut, Verstraeten, Aline, Luyckx, Ilse, Aziz, Hamza, Franco-Cereceda, Anders, Andelfinger, Gregor, Woods, Courtney E., Lin, Honghuang, Rose, Rebecca, Hughes, G. Chad, Lindsay, Mark E., Jaskula-Ranga, Vinod, Mertens, Luc, Isselbacher, Eric M., Bedja, Djahida, Butcher, Jonathan T., MacCarrick, Gretchen, Dietz, Harry C., Verhagen, Judith M. A., Cannaerts, Elyssa, Ellinor, Patrick T., Sparks, Elizabeth, Preuss, Christoph, Mohamed, Salah A., Lauridsen, Henrik

2019

Overview

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 nonsyndromic 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. Individuals with biscuspid aortic valve and ascending aortic aneurysm show enrichment of rare variants in ROBO4 . Functional studies suggest that ROBO4 mutations disrupt endothelial cell performance and contribute to pathological remodeling of aortic tissues.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/51 / 13/89 / 14/19 / 14/63 / 38/23 / 631/208 / 64/116 / 64/60 / 692/308/1426 / 692/699/75/1539 / Agriculture / Aneurysm / Aneurysms / Animal Genetics and Genomics / Animal models / Animals / Aortic aneurysm / Aortic Aneurysm, Thoracic - genetics / Aortic aneurysms / Aortic valve / Aortic Valve - abnormalities / Autosomal dominant inheritance / Bicuspid Aortic Valve Disease / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell adhesion & migration / Cell lines / Cells, Cultured / Congenital heart defects / Coronary vessels / CRISPR / Defects / Deoxyribonucleic acid / Development and progression / Disease Models, Animal / DNA / Endothelial cells / Endothelial Cells - physiology / Endothelium / Etiology / Etiology (Medicine) / Female / Gene Function / Gene mutation / Genes / Genetic aspects / Genetic disorders / Genomes / Genomics / Genotype & phenotype / Growth factors / Health aspects / Heart valve diseases / Heart Valve Diseases - genetics / Heredity / Human Genetics / Humans / Letter / Male / Medical research / Mesenchyme / Mice / Mice, Inbred C57BL / Mice, Knockout / Mutation / Mutation - genetics / Notch1 protein / Novels / Phenotype / Phenotypes / Receptors, Cell Surface - genetics / Rheumatic heart disease / Stem cells / Thorax / Zebrafish