ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.
Nat Genet 2019 Jan; 51(1):42-50.
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 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.
Gould, Russell A; Aziz, Hamza; Woods, Courtney E; Seman-Senderos, Manuel Alejandro; Sparks, Elizabeth; Preuss, Christoph; Wünnemann, Florian; Bedja, Djahida; Moats, Cassandra R; McClymont, Sarah A; Rose, Rebecca; Sobreira, Nara; Ling, Hua; MacCarrick, Gretchen; Kumar, Ajay Anand; Luyckx, Ilse; Cannaerts, Elyssa; Verstraeten, Aline; Björk, Hanna M; Lehsau, Ann-Cathrin; Jaskula-Ranga, Vinod; Lauridsen, Henrik; Shah, Asad A; Bennett, Christopher L; Ellinor, Patrick T; Lin, Honghuang; Isselbacher, Eric M; Lino Cardenas, Christian Lacks; Butcher, Jonathan T; Hughes, G Chad; Lindsay, Mark E; Mertens, Luc; Franco-Cereceda, Anders; Verhagen, Judith M A; Wessels, Marja; Mohamed, Salah A; Eriksson, Per; Mital, Seema; Van Laer, Lut; Loeys, Bart L; Andelfinger, Gregor; McCallion, Andrew S; and Dietz, Harry C, "ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm." (2019). Faculty Research 2019. 3.