Journal article
ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm
Nature genetics, v 51(1), pp 42-50
01 Jan 2019
PMID: 30455415
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm
- Creators
- Russell A Gould - Johns Hopkins MedicineHamza Aziz - Johns Hopkins MedicineCourtney E Woods - Johns Hopkins MedicineManuel Alejandro Seman-Senderos - Johns Hopkins MedicineElizabeth Sparks - Johns Hopkins MedicineChristoph Preuss - Jackson LaboratoryFlorian Wünnemann - Centre Hospitalier Universitaire Sainte-JustineDjahida Bedja - Johns Hopkins MedicineCassandra R Moats - Johns Hopkins MedicineSarah A McClymont - Johns Hopkins MedicineRebecca Rose - Johns Hopkins MedicineNara Sobreira - Johns Hopkins MedicineHua Ling - Johns Hopkins MedicineGretchen MacCarrick - Johns Hopkins MedicineAjay Anand Kumar - Antwerp University HospitalIlse Luyckx - Antwerp University HospitalElyssa Cannaerts - Antwerp University HospitalAline Verstraeten - Antwerp University HospitalHanna M Björk - Karolinska University HospitalAnn-Cathrin Lehsau - University of LübeckVinod Jaskula-Ranga - Johns Hopkins MedicineHenrik Lauridsen - Cornell UniversityAsad A Shah - Rex HospitalChristopher L Bennett - Johns Hopkins MedicinePatrick T Ellinor - Broad InstituteHonghuang Lin - Boston UniversityEric M Isselbacher - Massachusetts General HospitalChristian Lacks Lino Cardenas - Harvard Medical SchoolJonathan T Butcher - Cornell UniversityG Chad Hughes - Duke University HospitalMark E Lindsay - Massachusetts General HospitalLuc Mertens - Hospital for Sick ChildrenAnders Franco-Cereceda - Department of Molecular Medicine and Surgery, University Hospital Solna, Karolinska Institutet, Stockholm, SwedenJudith M A Verhagen - Erasmus MCMarja Wessels - University of TorontoSalah A Mohamed - University of LübeckPer Eriksson - Karolinska University HospitalSeema Mital - University of TorontoLut Van Laer - Antwerp University HospitalBart L Loeys - Antwerp University HospitalGregor Andelfinger - Jackson LaboratoryAndrew S McCallion - Johns Hopkins MedicineHarry C Dietz - Howard Hughes Medical InstituteBaylor-Hopkins Center for Mendelian Genomics
- Publication Details
- Nature genetics, v 51(1), pp 42-50
- Publisher
- Springer Nature
- Grant note
- S10 OD012287 / NIH HHS R01 HL110328 / NHLBI NIH HHS Howard Hughes Medical Institute T32 GM007814 / NIGMS NIH HHS U54 HG006542 / NHGRI NIH HHS P50 HD103538 / NICHD NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000454108800012
- Scopus ID
- 2-s2.0-85056989681
- Other Identifier
- 991021229993104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity