PUBLICATION
ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm
- Authors
- Gould, R.A., Aziz, H., Woods, C.E., Seman-Senderos, M.A., Sparks, E., Preuss, C., Wünnemann, F., Bedja, D., Moats, C.R., McClymont, S.A., Rose, R., Sobreira, N., Ling, H., MacCarrick, G., Kumar, A.A., Luyckx, I., Cannaerts, E., Verstraeten, A., Björk, H.M., Lehsau, A.C., Jaskula-Ranga, V., Lauridsen, H., Shah, A.A., Bennett, C.L., Ellinor, P.T., Lin, H., Isselbacher, E.M., Lino Cardenas, C.L., Butcher, J.T., Hughes, G.C., Lindsay, M.E., Baylor-Hopkins Center for Mendelian Genomics, MIBAVA Leducq Consortium, Mertens, L., Franco-Cereceda, A., Verhagen, J.M.A., Wessels, M., Mohamed, S.A., Eriksson, P., Mital, S., Van Laer, L., Loeys, B.L., Andelfinger, G., McCallion, A.S., Dietz, H.C.
- ID
- ZDB-PUB-190425-23
- Date
- 2019
- Source
- Nature Genetics 51: 42-50 (Journal)
- Registered Authors
- Ellinor, Patrick, McCallion, Andy
- Keywords
- none
- MeSH Terms
-
- Animals
- Aortic Aneurysm, Thoracic/genetics*
- Aortic Valve/abnormalities*
- Cells, Cultured
- Disease Models, Animal
- Endothelial Cells/physiology
- Female
- Heart Valve Diseases/genetics*
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mutation/genetics*
- Phenotype
- Receptors, Cell Surface/genetics*
- Zebrafish
- PubMed
- 30455415 Full text @ Nat. Genet.
Citation
Gould, R.A., Aziz, H., Woods, C.E., Seman-Senderos, M.A., Sparks, E., Preuss, C., Wünnemann, F., Bedja, D., Moats, C.R., McClymont, S.A., Rose, R., Sobreira, N., Ling, H., MacCarrick, G., Kumar, A.A., Luyckx, I., Cannaerts, E., Verstraeten, A., Björk, H.M., Lehsau, A.C., Jaskula-Ranga, V., Lauridsen, H., Shah, A.A., Bennett, C.L., Ellinor, P.T., Lin, H., Isselbacher, E.M., Lino Cardenas, C.L., Butcher, J.T., Hughes, G.C., Lindsay, M.E., Baylor-Hopkins Center for Mendelian Genomics, MIBAVA Leducq Consortium, Mertens, L., Franco-Cereceda, A., Verhagen, J.M.A., Wessels, M., Mohamed, S.A., Eriksson, P., Mital, S., Van Laer, L., Loeys, B.L., Andelfinger, G., McCallion, A.S., Dietz, H.C. (2019) ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nature Genetics. 51:42-50.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping