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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


NCBI Reference Sequence


  1. 1.

    & Noncommunicable diseases. N. Engl. J. Med. 369, 1336–1343 (2013).

  2. 2.

    et al. Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. Nat. Genet. 13, 98–100 (1996).

  3. 3.

    et al. A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly. Kidney Int. 53, 167–172 (1998).

  4. 4.

    et al. Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly. Stroke 28, 1749–1754 (1997).

  5. 5.

    Genetic dissection of human blood pressure variation: common pathways from rare phenotypes. Harvey Lect. 100, 71–101 (2004).

  6. 6.

    , , & Hereditary brachydactyly associated with hypertension. J. Med. Genet. 10, 253–259 (1973).

  7. 7.

    et al. Childhood hypertension in autosomal-dominant hypertension with brachydactyly. Hypertension 56, 988–994 (2010).

  8. 8.

    et al. Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. Hypertension 43, 471–476 (2004).

  9. 9.

    et al. Inversion region for hypertension and brachydactyly on chromosome 12p features multiple splicing and noncoding RNA. Hypertension 51, 426–431 (2008).

  10. 10.

    et al. Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p. Hum. Mol. Genet. 12, 1273–1277 (2003).

  11. 11.

    et al. Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol. Pharmacol. 64, 533–546 (2003).

  12. 12.

    et al. Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J. Bone Miner. Res. 17, 249–256 (2002).

  13. 13.

    et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90, 740–745 (2012).

  14. 14.

    et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum. Genet. 90, 746–751 (2012).

  15. 15.

    et al. A misplaced lncRNA causes brachydactyly in humans. J. Clin. Invest. 122, 3990–4002 (2012).

  16. 16.

    , , & Regulation of adenylate cyclase of human platelet membranes by forskolin. J. Biol. Chem. 257, 7485–7490 (1982).

  17. 17.

    , , & Formation of nitric oxide from l-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc. Natl. Acad. Sci. USA 86, 5159–5162 (1989).

  18. 18.

    et al. Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes. J. Biol. Chem. 277, 38072–38078 (2002).

  19. 19.

    et al. Selective regulation of cyclic nucleotide phosphodiesterase PDE3A isoforms. Proc. Natl. Acad. Sci. USA 110, 19778–19783 (2013).

  20. 20.

    et al. Identification of a novel isoform of the cyclic-nucleotide phosphodiesterase PDE3A expressed in vascular smooth-muscle myocytes. Biochem. J. 353, 41–50 (2001).

  21. 21.

    et al. Comparison of the effects of cilostazol and milrinone on intracellular cAMP levels and cellular function in platelets and cardiac cells. J. Cardiovasc. Pharmacol. 34, 497–504 (1999).

  22. 22.

    et al. Reduced phosphodiesterase 3 activity and phosphodiesterase 3A level in synthetic vascular smooth muscle cells: implications for use of phosphodiesterase 3 inhibitors in cardiovascular tissues. Mol. Pharmacol. 61, 1033–1040 (2002).

  23. 23.

    et al. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N. Engl. J. Med. 364, 2218–2226 (2011).

  24. 24.

    & Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28, 585–596 (2010).

  25. 25.

    , & Phosphodiesterase 3A (PDE3A) deletion suppresses proliferation of cultured murine vascular smooth muscle cells (VSMCs) via inhibition of mitogen-activated protein kinase (MAPK) signaling and alterations in critical cell cycle regulatory proteins. J. Biol. Chem. 286, 26238–26249 (2011).

  26. 26.

    et al. Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension. Hypertension 28, 1085–1092 (1996).

  27. 27.

    , & Protein kinase C–mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets. J. Biol. Chem. 284, 12339–12348 (2009).

  28. 28.

    , , & Phosphodiesterase 3A binds to 14-3-3 proteins in response to PMA-induced phosphorylation of Ser428. Biochem. J. 392, 163–172 (2005).

  29. 29.

    et al. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257, 7847–7851 (1982).

  30. 30.

    et al. Protein kinase A antagonizes platelet-derived growth factor–induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc. Natl. Acad. Sci. USA 90, 10300–10304 (1993).

  31. 31.

    , , & Increased phosphodiesterase 3A/4B expression after angioplasty and the effect on VASP phosphorylation. Eur. J. Pharmacol. 590, 29–35 (2008).

  32. 32.

    , & Endogenous parathyroid hormone–related protein regulates the expression of PTH type 1 receptor and proliferation of vascular smooth muscle cells. Mol. Endocrinol. 23, 1681–1690 (2009).

  33. 33.

    et al. Glycogen synthase kinase 3β interaction protein functions as an A-kinase anchoring protein. J. Biol. Chem. 285, 5507–5521 (2010).

  34. 34.

    et al. Phosphodiesterase type 3A regulates basal myocardial contractility through interacting with sarcoplasmic reticulum calcium ATPase type 2a signaling complexes in mouse heart. Circ. Res. 112, 289–297 (2013).

  35. 35.

    et al. AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmic reticulum. EMBO Rep. 8, 1061–1067 (2007).

  36. 36.

    et al. Regulation of SERCA2 activity by PDE3A in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2. J. Biol. Chem. 290, 6763–6776 (2015).

  37. 37.

    , , & Milrinone for persistent pulmonary hypertension of the newborn. Cochrane Database Syst. Rev. CD007802 (2010).

  38. 38.

    Invited review: regulation of myosin phosphorylation in smooth muscle. J. Appl. Physiol. 91, 497–503 (2001).

  39. 39.

    et al. Deletion and point mutations of PTHLH cause brachydactyly type E. Am. J. Hum. Genet. 86, 434–439 (2010).

  40. 40.

    et al. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc. Natl. Acad. Sci. USA 101, 14794–14799 (2004).

  41. 41.

    , & Differential regulation of the parathyroid hormone–related protein gene P1 and P3 promoters by cAMP. Mol. Cell. Endocrinol. 138, 173–184 (1998).

  42. 42.

    et al. Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78–81 (2010).

  43. 43.

    et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

  44. 44.

    , & ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

  45. 45.

    & GeneTalk: an expert exchange platform for assessing rare sequence variants in personal genomes. Bioinformatics 28, 2515–2516 (2012).

  46. 46.

    et al. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat. Methods 6, 677–681 (2009).

  47. 47.

    et al. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am. J. Hum. Genet. 91, 629–635 (2012).

  48. 48.

    , & Isolation and large scale expansion of adult human endothelial colony forming progenitor cells. J. Vis. Exp. 32, 1524 (2009).

  49. 49.

    et al. High-affinity AKAP7δ–protein kinase A interaction yields novel protein kinase A–anchoring disruptor peptides. Biochem. J. 396, 297–306 (2006).

  50. 50.

    , & Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences. Nat. Protoc. 2, 3247–3256 (2007).

  51. 51.

    et al. Compartmentalization of cAMP-dependent signaling by phosphodiesterase-4D is involved in the regulation of vasopressin-mediated water reabsorption in renal principal cells. J. Am. Soc. Nephrol. 18, 199–212 (2007).

  52. 52.

    et al. Highly functionalized terpyridines as competitive inhibitors of AKAP-PKA interactions. Angew. Chem. Int. Edn Engl. 52, 12187–12191 (2013).

  53. 53.

    et al. Small molecule AKAP–protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes. J. Biol. Chem. 286, 9079–9096 (2011).

  54. 54.

    , , , & New universal primers facilitate Pyrosequencing. Electrophoresis 27, 394–397 (2006).

  55. 55.

    et al. A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E. Hum. Mol. Genet. 19, 848–860 (2010).

Download references


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.


  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


  1. Search for Philipp G Maass in:

  2. Search for Atakan Aydin in:

  3. Search for Friedrich C Luft in:

  4. Search for Carolin Schächterle in:

  5. Search for Anja Weise in:

  6. Search for Sigmar Stricker in:

  7. Search for Carsten Lindschau in:

  8. Search for Martin Vaegler in:

  9. Search for Fatimunnisa Qadri in:

  10. Search for Hakan R Toka in:

  11. Search for Herbert Schulz in:

  12. Search for Peter M Krawitz in:

  13. Search for Dmitri Parkhomchuk in:

  14. Search for Jochen Hecht in:

  15. Search for Irene Hollfinger in:

  16. Search for Yvette Wefeld-Neuenfeld in:

  17. Search for Eireen Bartels-Klein in:

  18. Search for Astrid Mühl in:

  19. Search for Martin Kann in:

  20. Search for Herbert Schuster in:

  21. Search for David Chitayat in:

  22. Search for Martin G Bialer in:

  23. Search for Thomas F Wienker in:

  24. Search for Jürg Ott in:

  25. Search for Katharina Rittscher in:

  26. Search for Thomas Liehr in:

  27. Search for Jens Jordan in:

  28. Search for Ghislaine Plessis in:

  29. Search for Jens Tank in:

  30. Search for Knut Mai in:

  31. Search for Ramin Naraghi in:

  32. Search for Russell Hodge in:

  33. Search for Maxwell Hopp in:

  34. Search for Lars O Hattenbach in:

  35. Search for Andreas Busjahn in:

  36. Search for Anita Rauch in:

  37. Search for Fabrice Vandeput in:

  38. Search for Maolian Gong in:

  39. Search for Franz Rüschendorf in:

  40. Search for Norbert Hübner in:

  41. Search for Hermann Haller in:

  42. Search for Stefan Mundlos in:

  43. Search for Nihat Bilginturan in:

  44. Search for Matthew A Movsesian in:

  45. Search for Enno Klussmann in:

  46. Search for Okan Toka in:

  47. Search for Sylvia Bähring in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Tables 1–3.

About this article

Publication history





Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing