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Title
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ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm
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Author
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Institution/Organisation
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Baylor-Hopkins Ctr Mendelian
MIBAVA Leducq Consortium
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Abstract
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| 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 non-syndromic BAV cases with and without AscAA(5-8), 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. |
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Language
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English
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Source (journal)
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Nature genetics. - New York, N.Y.
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Publication
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New York, N.Y.
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2019
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ISSN
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1061-4036
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DOI
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10.1038/S41588-018-0265-Y
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Volume/pages
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51
:1
(2019)
, p. 42-50
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ISI
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000454108800012
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Pubmed ID
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30455415
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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