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 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, RA; Aziz, H; Woods, CE; Seman-Senderos, MA; Sparks, E; Preuss, C; Wünnemann, F; Bedja, D; Moats, CR; McClymont, SA; Rose, R; Sobreira, N; Ling, H; MacCarrick, G; Kumar, AA; Luyckx, I; Cannaerts, E; Verstraeten, A; Björk, HM; Lehsau, A-C; Jaskula-Ranga, V; Lauridsen, H; Shah, AA; Bennett, CL; Ellinor, PT; Lin, H; Isselbacher, EM; Lino Cardenas, CL; Butcher, JT; Hughes, GC; Lindsay, ME; Baylor-Hopkins Center for Mendelian Genomics, ; MIBAVA Leducq Consortium, ; Mertens, L; Franco-Cereceda, A; Verhagen, JMA; Wessels, M; Mohamed, SA; Eriksson, P; Mital, S; Van Laer, L; Loeys, BL; Andelfinger, G; McCallion, AS; Dietz, HC
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