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Abstract

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor1. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB)2. The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated3,4. In vitro analyses of mesenchymal stem cell–derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A–mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

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Acknowledgements

We thank all family members for their cooperation. We thank M.-B. Köhler and M. Toliat for technical assistance. P.G.M., F.C.L., O.T. and S.B. received support from the Deutsche Forschungsgemeinschaft (DFG; BA1773/4-1, BA1773/4-2, MA5028/1-2 and MA5028/1-3) and grants-in-aid from the German Hypertension Society (Deutsche Hochdruckliga, DHL) and from the German Heart Research Foundation (F/24/13). E.K. was supported by the DFG (KL1415/4-2), the Else Kröner-Fresenius-Stiftung (2013_A145) and the German-Israeli Foundation (I-1210-286.13/2012). F.C.L. received support from the Lingen-Stiftung. F.V. and M.A.M. were supported by the US Department of Veterans Affairs (CARA-029-09F), the American Heart Association (10034439) and the University of Utah Research Foundation. James C. Melby referred one of the families. Dr. Melby died on 19 August 2007.

Author information

Author notes

    • Philipp G Maass

    Present address: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Philipp G Maass
    • , Atakan Aydin
    • , Friedrich C Luft
    • , Carolin Schächterle
    •  & Sylvia Bähring

    These authors contributed equally to this work.

Affiliations

  1. Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

    • Philipp G Maass
    • , Atakan Aydin
    • , Friedrich C Luft
    • , Martin Vaegler
    • , Fatimunnisa Qadri
    • , Knut Mai
    • , Maolian Gong
    •  & Sylvia Bähring
  2. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

    • Philipp G Maass
    • , Atakan Aydin
    • , Friedrich C Luft
    • , Carolin Schächterle
    • , Fatimunnisa Qadri
    • , Herbert Schulz
    • , Irene Hollfinger
    • , Yvette Wefeld-Neuenfeld
    • , Eireen Bartels-Klein
    • , Astrid Mühl
    • , Russell Hodge
    • , Maolian Gong
    • , Franz Rüschendorf
    • , Norbert Hübner
    • , Enno Klussmann
    •  & Sylvia Bähring
  3. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Friedrich C Luft
  4. Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

    • Anja Weise
    • , Katharina Rittscher
    •  & Thomas Liehr
  5. Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Sigmar Stricker
    • , Peter M Krawitz
    • , Dmitri Parkhomchuk
    • , Jochen Hecht
    • , Thomas F Wienker
    •  & Stefan Mundlos
  6. Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.

    • Sigmar Stricker
  7. Department of Nephrology, Hannover University Medical School, Hannover, Germany.

    • Carsten Lindschau
    •  & Hermann Haller
  8. Staatliche Technikerschule Berlin, Berlin, Germany.

    • Carsten Lindschau
  9. Department of Urology, Laboratory of Tissue Engineering, Eberhard Karls University Tübingen, Tübingen, Germany.

    • Martin Vaegler
  10. Division of Nephrology and Hypertension, Eastern Virginia Medical School, Norfolk, Virginia, USA.

    • Hakan R Toka
  11. Division of Nephrology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Hakan R Toka
  12. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.

    • Herbert Schulz
  13. Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Peter M Krawitz
    • , Dmitri Parkhomchuk
    •  & Stefan Mundlos
  14. Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Peter M Krawitz
    • , Dmitri Parkhomchuk
    • , Jochen Hecht
    •  & Stefan Mundlos
  15. Department II of Medicine, University of Cologne, Cologne, Germany.

    • Martin Kann
  16. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

    • Martin Kann
  17. INFOGEN, Berlin, Germany.

    • Herbert Schuster
  18. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • David Chitayat
  19. Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

    • David Chitayat
  20. Division of Medical Genetics, North Shore/LIJ Health System, Manhasset, New York, USA.

    • Martin G Bialer
  21. Department of Pediatrics, North Shore/LIJ Health System, Manhasset, New York, USA.

    • Martin G Bialer
  22. Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

    • Thomas F Wienker
  23. Institute of Psychology, Chinese Academy of Sciences, Beijing, China.

    • Jürg Ott
  24. Statistical Genetics, Rockefeller University, New York, New York, USA.

    • Jürg Ott
  25. Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.

    • Jens Jordan
    •  & Jens Tank
  26. Centre Hospitalier Universitaire de Caen, Cytogénétique Postnatale et Génétique Clinique, Caen, France.

    • Ghislaine Plessis
  27. Department of Neurosurgery, Bundeswehrkrankenhaus Ulm, Ulm, Germany.

    • Ramin Naraghi
  28. Department of Pediatrics, Griffith Base Hospital, Griffith, New South Wales, Australia.

    • Maxwell Hopp
  29. Department of Ophthalmology, Hospital Ludwigshafen, Ludwigshafen, Germany.

    • Lars O Hattenbach
  30. HealthTwist, Berlin, Germany.

    • Andreas Busjahn
  31. Institute for Medical Genetics, University of Zurich, Zurich, Switzerland.

    • Anita Rauch
  32. Cardiology Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA.

    • Fabrice Vandeput
    •  & Matthew A Movsesian
  33. Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.

    • Fabrice Vandeput
    •  & Matthew A Movsesian
  34. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.

    • Fabrice Vandeput
    •  & Matthew A Movsesian
  35. DZHK (German Centre for Cardiovascular Research), Berlin, Germany.

    • Norbert Hübner
    •  & Enno Klussmann
  36. Charité Universitätsmedizin, Berlin, Germany.

    • Norbert Hübner
  37. Department of Pediatric Oncology, Hacettepe University, Ankara, Turkey.

    • Nihat Bilginturan
  38. Department of Pediatric Cardiology, Children's Hospital, Friedrich Alexander University Erlangen, Erlangen, Germany.

    • Okan Toka

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Contributions

N.B. first described this syndrome in 1973. F.C.L. and his laboratory have pursued this project since 1994. O.T., H.R.T., H. Schuster, J.J., J.T., H.H., R.H., L.O.H. and R.N. phenotyped the syndrome. D.C., M.G.B., G.P., M.H. and H.R.T. identified additional families with the syndrome. T.F.W., J.O., S.B., A.B. and F.R. performed microsatellite and SNP linkage analyses. M.G. and N.H. performed genotyping analyses within the families and also analyzed Chinese hypertensive families that showed linkage to the chromosome 12p locus. A.W., M.K., A.R., K.R. and T.L. performed cytogenetics. S.S. performed in situ mouse studies. S.M., P.M.K., D.P. and J.H. carried out Illumina whole-genome sequencing. A.A., P.G.M. and S.B. analyzed Complete Genomics whole-genome sequencing data, and A.A. identified the PDE3A mutation. H. Schulz statistically analyzed various data. C.L. and A.A. performed the confocal immunofluorescence imaging. F.Q., I.H., E.B.-K. and A.M. performed technical studies. K.M. and Y.W.-N. prepared MSCs. M.V. kindly provided unaffected MSCs and supported all the MSC investigations. Y.W.-N., A.A. and P.G.M. analyzed cell proliferation. F.V. and M.A.M. provided Flag-tagged PDE3A expression constructs and provided intellectual input. C.S. and E.K. performed ELISA assays on recombinant proteins and peptide SPOT assays. P.G.M. participated in all scientific aspects of the study and was personally responsible for the PDE3A functional assays, IC50 determinations and work with MSCs. P.G.M., F.C.L. and S.B. wrote the manuscript. The manuscript was the product of more than 20 years of research to which all authors have contributed.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Friedrich C Luft.

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https://doi.org/10.1038/ng.3302

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