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

TitleROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.
Publication TypeJournal Article
Year of Publication2019
AuthorsGould, RA, Aziz, H, Woods, CE, Seman-Senderos, MAlejandro, Sparks, E, Preuss, C, Wünnemann, F, Bedja, D, Moats, CR, McClymont, SA, Rose, R, Sobreira, N, Ling, H, MacCarrick, G, Kumar, AAnand, 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, Cardenas, CLacks Lino, Butcher, JT, G Hughes, C, Lindsay, ME, 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
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics, MIBAVA Leducq consortium
JournalNat Genet
Date Published2019 01
KeywordsAnimals, Aortic Aneurysm, Thoracic, Aortic Valve, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Heart Valve Diseases, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Receptors, Cell Surface, Zebrafish

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) that frequently presents with ascending aortic aneurysm (AscAA). 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, 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.

Alternate JournalNat. Genet.
PubMed ID30455415
PubMed Central IDPMC6309588
Grant List / HH / Howard Hughes Medical Institute / United States
T32 GM007814 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States