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

Nat Genet. 2019 Jan;51(1):42-50. Epub 2018 Nov 19
Russell A Gould 1 , Hamza Aziz 1 , Courtney E Woods 2 , Manuel Alejandro Seman-Senderos 2 , Elizabeth Sparks 2 , Christoph Preuss 3 , Florian Wünnemann 4 , Djahida Bedja 5 , Cassandra R Moats 6 , Sarah A McClymont 7 , Rebecca Rose 2 , Nara Sobreira 2 , Hua Ling 7 , Gretchen MacCarrick 2 , Ajay Anand Kumar 8 , Ilse Luyckx 8 , Elyssa Cannaerts 8 , Aline Verstraeten 8 , Hanna M Björk 9 , Ann-Cathrin Lehsau 10 , Vinod Jaskula-Ranga 11 , Henrik Lauridsen 12 , Asad A Shah 13 , Christopher L Bennett 1 , Patrick T Ellinor 14 , Honghuang Lin 15 , Eric M Isselbacher 16 , Christian Lacks Lino Cardenas 17 , Jonathan T Butcher 12 , G Chad Hughes 18 , Mark E Lindsay 19 , Baylor-Hopkins Center for Mendelian Genomics , MIBAVA Leducq Consortium , Luc Mertens 20 , Anders Franco-Cereceda 21 , Judith M A Verhagen 22 , Marja Wessels 23 , Salah A Mohamed 10 , Per Eriksson 9 , Seema Mital 23 , Lut Van Laer 8 , Bart L Loeys 24 , Gregor Andelfinger 25 , Andrew S McCallion 26 , Harry C Dietz 27
Russell A Gould 1 , Hamza Aziz 1 , Courtney E Woods 2 , Manuel Alejandro Seman-Senderos 2 , Elizabeth Sparks 2 , Christoph Preuss 3 , Florian Wünnemann 4 , Djahida Bedja 5 , Cassandra R Moats 6 , Sarah A McClymont 7 , Rebecca Rose 2 , Nara Sobreira 2 , Hua Ling 7 , Gretchen MacCarrick 2 , Ajay Anand Kumar 8 , Ilse Luyckx 8 , Elyssa Cannaerts 8 , Aline Verstraeten 8 , Hanna M Björk 9 , Ann-Cathrin Lehsau 10 , Vinod Jaskula-Ranga 11 , Henrik Lauridsen 12 , Asad A Shah 13 , Christopher L Bennett 1 , Patrick T Ellinor 14 , Honghuang Lin 15 , Eric M Isselbacher 16 , Christian Lacks Lino Cardenas 17 , Jonathan T Butcher 12 , G Chad Hughes 18 , Mark E Lindsay 19 , Baylor-Hopkins Center for Mendelian Genomics , MIBAVA Leducq Consortium , Luc Mertens 20 , Anders Franco-Cereceda 21 , Judith M A Verhagen 22 , Marja Wessels 23 , Salah A Mohamed 10 , Per Eriksson 9 , Seema Mital 23 , Lut Van Laer 8 , Bart L Loeys 24 , Gregor Andelfinger 25 , Andrew S McCallion 26 , Harry C Dietz 27
+ et al

[No authors listed]

Author information
  • 1 Howard Hughes Medical Institute, Baltimore, MD, USA.
  • 2 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 The Jackson Laboratory, Bar Harbor, ME, USA.
  • 4 Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
  • 5 Heart and Vascular Institute, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Oregon National Primate Research Center, Portland, OR, USA.
  • 7 Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8 Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium.
  • 9 Center for Molecular Medicine, Department of Medicine Solna, University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
  • 10 Department of Cardiac and Thoracic Vascular Surgery, University Hospital Lübeck, Lübeck, Germany.
  • 11 Wilmer Eye Institute in the Department of Ophthalmology at the Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 12 The Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
  • 13 Rex Hospital, Raleigh, NC, USA.
  • 14 Cardiovascular Research Institute, Massachussets General Hospital, Charlestown, MA, USA.
  • 15 Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
  • 16 Thoracic Aortic Center, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 17 Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 18 Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, USA.
  • 19 Thoracic Aortic Center and Cardiovascular Genetics Program, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 20 Division of Cardiology, The Hospital for Sick Children, Labatt Family Heart Centre, Toronto, Ontario, Canada.
  • 21 Department of Molecular Medicine and Surgery, University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
  • 22 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • 23 Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • 24 Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 25 Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
  • 26 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. andy@jhmi.edu.
  • 27 Department of Pediatrics, Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hdietz@jhmi.edu.

摘要

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.

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