ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. (January 2019)

• Record Type: Journal Article
• Authors: Gould, Russell; Aziz, Hamza; Woods, Courtney; Seman-Senderos, Manuel; Sparks, Elizabeth; Preuss, Christoph; Wünnemann, Florian; Bedja, Djahida; Moats, Cassandra; McClymont, Sarah; Rose, Rebecca; Sobreira, Nara; Ling, Hua; MacCarrick, Gretchen; Kumar, Ajay; Luyckx, Ilse; Cannaerts, Elyssa; Verstraeten, Aline; Björk, Hanna; Lehsau, Ann-Cathrin; Jaskula-Ranga, Vinod; Lauridsen, Henrik; Shah, Asad; Bennett, Christopher; Ellinor, Patrick; Lin, Honghuang; Isselbacher, Eric; Lino Cardenas, Christian; Butcher, Jonathan; Hughes, G.; Lindsay, Mark; Mertens, Luc; Franco-Cereceda, Anders; Verhagen, Judith; Wessels, Marja; Mohamed, Salah; Eriksson, Per; Mital, Seema; Laer, Lut; Loeys, Bart; Andelfinger, Gregor; McCallion, Andrew; Dietz, Harry;
• Is Part Of: Nature genetics. Volume 51:Number 1(2019)
• Page Start: 42
• Page End: 50
• Publication Date: 2019-01
• Subjects: Human genetics -- Periodicals; 576.505
• DOI: 10.1038/s41588-018-0265-y
• Languages: English
• ISSNs: 1061-4036

Abstract

Abstract 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 AscAA5–8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants inROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing ofROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing ofROBO4 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 inROBO4 . Functional studies suggest thatROBO4 mutations disrupt endothelial cell performance and contribute to pathological remodeling of aortic tissues.