Abstract

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1,2,3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1+/− mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

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Acknowledgements

This work was supported by the Fondation Leducq (Paris, France) Mitral Transatlantic Network of Excellence grant 07CVD04. MVP patient studies were supported by an Innovation in Clinical Research award of the Doris Duke Charitable Foundation, by an award of the Aetna Quality Care Research Fund, and by a gift from Rena M. Shulsky, New York, New York (S.A.S. and R.A.L.). Sequencing of the candidate region was performed at the Venter Institute through a grant from the National Heart Lung and Blood Institute Resequencing and Genotyping (RS&G) Service (S.A.S.). The work at MUSC was performed in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Collection of the MVP France cohort was supported by the French Society of Cardiology. Other funding sources: National Heart Lung and Blood Institute: R01HL122906-01 (A.W.), R01-HL33756 (R.R.M.), COBRE 1P30 GM103342 (R.R.M., R.A.N., A.W.), 8P20 GM103444-07 (R.R.M. and R.A.N.), R01-HL109004 (D.J.M.), R01-HL127692 (D.J.M., S.A.S., R.A.N., R.A.L.); RO1-HL095696 (D.R.M.), VA Merit Review BX002327 (D.R.M.); National Institute of Mental Health R00-MH095867 (M.E.T.) The Hassenfeld Scholar Program (D.J.M.); The March of Dimes (M.E.T.); M.G.H. Scholars Program (S.A.S., M.E.T.); American Heart Association: 09GRNT2060075 (A.W.), 11SDG5270006 (R.A.N.), 2261354 (D.J.M.), 15GRNT25080052 (R.A.N.); National Science Foundation: EPS-0903795 (R.R.M.); NHLBI K24 HL67434, R01HL72265 and R01HL109506 and the Ellison Foundation, Boston, MA (R.A.L.), Howard Hughes Medical Institute (K.D.I.), and a gift from Michael Zak (D.J.M.). Thanks to T. Brown (MUSC) for his guidance on MRI studies, C. Hanscom (M.G.H.) for assistance with genomic libraries, and E. Lim (H.M.S.) for contributions in interpreting the exome mutation data. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.

Author information

Author notes

    • Ronen Durst
    • , Kimberly Sauls
    •  & David S. Peal

    These authors contributed equally to this work.

    • Xavier Jeunemaitre
    • , Albert Hagege
    • , Robert A. Levine
    • , David J. Milan
    • , Russell A. Norris
    •  & Susan A. Slaugenhaupt

    These authors jointly supervised this work.

Affiliations

  1. Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA

    • Ronen Durst
    • , Maire Leyne
    • , Monica Salani
    • , Michael E. Talkowski
    • , Harrison Brand
    • , Charles Simpson
    • , Christopher Jett
    • , Matthew R. Stone
    • , Florie Charles
    • , Colby Chiang
    • , David J. Milan
    •  & Susan A. Slaugenhaupt
  2. Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000 Jerusalem, Israel

    • Ronen Durst
  3. Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA

    • Kimberly Sauls
    • , Annemarieke deVlaming
    • , Katelynn Toomer
    • , Andy Wessels
    • , Tahirali Motiwala
    • , Katherine Williams
    • , Amanda Johnson
    • , Roger R. Markwald
    •  & Russell A. Norris
  4. Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA

    • David S. Peal
    • , Stacey N. Lynch
    •  & David J. Milan
  5. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Michael E. Talkowski
    •  & Harrison Brand
  6. INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France

    • Maëlle Perrocheau
    • , Nabila Bouatia-Naji
    • , Xavier Jeunemaitre
    •  & Albert Hagege
  7. Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France

    • Nabila Bouatia-Naji
    • , Xavier Jeunemaitre
    • , Albert Hagege
    •  & Robert A. Levine
  8. Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Francesca N. Delling
  9. Yale-New Haven Hospital Heart and Vascular Center, Yale School of Medicine, 20 York Street, New Haven, Connecticut 06510, USA

    • Lisa A. Freed
  10. Department of Cardiology, University Hospital Amiens; INSERM U-1088, Jules Verne University of Picardie, 80000 Amiens, France

    • Christophe Tribouilloy
  11. Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France

    • Thierry Le Tourneau
    • , Hervé LeMarec
    • , Christian Dina
    •  & Jean-Jacques Schott
  12. Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), 28029 Madrid, Spain

    • Leticia Fernandez-Friera
    •  & Jorge Solis
  13. Hospital Universitario Monteprincipe, 28660 Madrid, Spain

    • Leticia Fernandez-Friera
    •  & Jorge Solis
  14. Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain

    • Daniel Trujillano
    •  & Xavier Estivill
  15. Universitat Pompeu Fabra (UPF), 08002 Barcelona, Catalonia, Spain

    • Daniel Trujillano
    • , Stephan Ossowski
    •  & Xavier Estivill
  16. Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Catalonia, Spain

    • Daniel Trujillano
    •  & Xavier Estivill
  17. CIBER in Epidemiology and Public Health (CIBERESP), 08036 Barcelona, Catalonia, Spain

    • Daniel Trujillano
    •  & Xavier Estivill
  18. Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain

    • Stephan Ossowski
  19. CNRS, UMR 6291, 44007 Nantes, France

    • Christian Dina
    •  & Jean-Jacques Schott
  20. Université de Nantes, 44322 Nantes, France

    • Christian Dina
    •  & Jean-Jacques Schott
  21. CHU Nantes, l’Institut du Thorax, Service de Cardiologie, 44093 Nantes, France

    • Christian Dina
    •  & Jean-Jacques Schott
  22. Service d'Anatomie Pathologique, Hôpital Européen Georges Pompidou, 75015 Paris, France

    • Patrick Bruneval
  23. National Heart and Lung Institute, Harefield, Heart Science Centre, Imperial College London, London SW7 2AZ, UK

    • Adrian Chester
  24. Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA

    • Kenneth D. Irvine
    •  & Yaopan Mao
  25. INSERM UMR_S910, Team physiopathology of cardiac development Aix-Marseille University, Medical School La Timone, 13885 Marseille, France

    • Michel Puceat
  26. Department of Cellular and Molecular Biology, University of Texas Health Science Center Northeast Tyler, Texas75708, USA

    • Yoshikazu Tsukasaki
  27. Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA

    • Donald R. Menick
    •  & Harinath Kasiganesan
  28. Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA

    • Xingju Nie
    •  & Ann-Marie Broome
  29. Assistance Publique – Hôpitaux de Paris, Département de Génétique, Hôpital Européen Georges Pompidou, 75015 Paris, France

    • Xavier Jeunemaitre
  30. Assistance Publique – Hôpitaux de Paris, Département de Cardiologie, Hôpital Européen Georges Pompidou, 75015 Paris, France

    • Albert Hagege
  31. Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA

    • Robert A. Levine

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Contributions

R.D., M.L., C.S., C.J., M.P., X.J., J.-J.S., D.T., S.O., X.E., F.C., and S.A.S. participated in genetic analysis, sequencing and mutation cloning. R.D., F.N.D., L.A.F., T.L.T., H.L.M., L.F.-F., J.S., C.T., R.A.L., and A.H. participated in patient collection and phenotyping using echocardiography. D.S.P., S.N.L. and D.J.M. performed zebrafish and cell culture experiments. M.E.T., M.R.S., N.B.N., C.D., H.B. and C.C. performed bioinformatics and statistical analysis. A.C., P.C., and P.B. established human patient cell cultures and histology on human tissues. A.d.V., K.W., K.D.I., Y.M., K.S., A.W., T.M., K.T., R.R.M. and R.A.N. performed mouse embryo and knockout experiments and cell alignment and migration assays. X.N., A.-M.B., D.R.M., H.K. performed mouse in vivo imaging. R.D., D.J.M., R.A.L., R.A.N. and S.A.S. wrote the manuscript. R.A.L., A.H., S.A.S. and J.J.S. coordinated the Leducq Mitral Network.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Russell A. Norris or Susan A. Slaugenhaupt.

Extended data

Supplementary information

Videos

  1. 1.

    Parasternal long-axis view of family 1 proband

    This video shows posterior leaflet prolapse and dilated left-heart chambers.

  2. 2.

    Zoomed view of thickened, prolapsing leaflet in family 1 proband.

    This video shows thickened, prolapsing leaflet in family 1 proband.

  3. 3.

    Doppler color flow mapping of family proband 1

    This video shows severe MR, increasing with prolapse throughout systole.

  4. 4.

    High-speed video of wild type (control injected) D. rerio heart at 72 hours post-fertilization (hpf).

    At this stage the heart has looped and blood flow is unidirectional from the atrium (upper right) to the ventricle, and a constriction has formed at the junction between the atrium and ventricle. No regurgitation is evident.

  5. 5.

    High-speed video of dchs1b morphant D. rerio heart at 72 hpf.

    Hearts of dchs1b morphants fail to loop properly and there is regurgitation of blood from the ventricle (lower right) into the atrium (upper left). Concomitant with this phenotype, there is reduced constriction of the AV canal.

  6. 6.

    Parasternal long axis view of adult (9-month old) Dchs1+/+ heart

    This video shows normal mitral valve opening and closing.

  7. 7.

    Parasternal long-axis view of adult (9-month old) Dchs1+/- heart

    This video shows anterior and posterior leaflet thickening and posterior leaflet prolapse. Prolapse is most easily observed at frames: 149, 188, and 300

  8. 8.

    This video comprises 2 clips, which show 3D reconstructions of Dchs1+/+ 9, and Dchs1+/- 9-month old posterior leaflet

    Each of the clips shown were obtained from the micro-MRI slices.

  9. 9.

    AMIRA 3D reconstruction of Dchs1+/+, Dchs1+/-, and Dchs1-/- E17.5 mitral leaflets.

    Respective 3D reconstructions are shown sequentially during the movie. Green=Anterior Leaflet, Blue =Posterior Leaflet.

  10. 10.

    AMIRA 3D reconstruction of EPDC lineage trace in Dchs1+/+ and Dchs1+/- PO posterior mitral leaflets.

    Respective 3D reconstructions are shown sequentially during the movie. Green=EPDC, Blue =non-EPDCs

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https://doi.org/10.1038/nature14670

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