2. Academic Validation
  3. PDE3A mutations cause autosomal dominant hypertension with brachydactyly

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

  • Nat Genet. 2015 Jun;47(6):647-53. doi: 10.1038/ng.3302.
Philipp G Maass 1,  Atakan Aydin 1,  Friedrich C Luft 2,  Carolin Schächterle 3,  Anja Weise 4,  Sigmar Stricker 5,  Carsten Lindschau 6,  Martin Vaegler 7,  Fatimunnisa Qadri 1,  Hakan R Toka 8,  Herbert Schulz 9,  Peter M Krawitz 10,  Dmitri Parkhomchuk 10,  Jochen Hecht 11,  Irene Hollfinger 3,  Yvette Wefeld-Neuenfeld 3,  Eireen Bartels-Klein 3,  Astrid Mühl 3,  Martin Kann 12,  Herbert Schuster 13,  David Chitayat 14,  Martin G Bialer 15,  Thomas F Wienker 16,  Jürg Ott 17,  Katharina Rittscher 4,  Thomas Liehr 4,  Jens Jordan 18,  Ghislaine Plessis 19,  Jens Tank 18,  Knut Mai 20,  Ramin Naraghi 21,  Russell Hodge 3,  Maxwell Hopp 22,  Lars O Hattenbach 23,  Andreas Busjahn 24,  Anita Rauch 25,  Fabrice Vandeput 26,  Maolian Gong 1,  Franz Rüschendorf 3,  Norbert Hübner 27,  Hermann Haller 28,  Stefan Mundlos 10,  Nihat Bilginturan 29,  Matthew A Movsesian 26,  Enno Klussmann 30,  Okan Toka 31,  Sylvia Bähring 1
Affiliations

Affiliations

  • 1 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. [2] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
  • 2 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. [2] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [3] Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • 3 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
  • 4 Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
  • 5 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
  • 6 1] Department of Nephrology, Hannover University Medical School, Hannover, Germany. [2] Staatliche Technikerschule Berlin, Berlin, Germany.
  • 7 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. [2] Department of Urology, Laboratory of Tissue Engineering, Eberhard Karls University Tübingen, Tübingen, Germany.
  • 8 1] Division of Nephrology and Hypertension, Eastern Virginia Medical School, Norfolk, Virginia, USA. [2] Division of Nephrology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 9 1] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [2] Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 10 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany. [3] Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
  • 11 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
  • 12 1] Department II of Medicine, University of Cologne, Cologne, Germany. [2] Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • 13 INFOGEN, Berlin, Germany.
  • 14 1] Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • 15 1] Division of Medical Genetics, North Shore/LIJ Health System, Manhasset, New York, USA. [2] Department of Pediatrics, North Shore/LIJ Health System, Manhasset, New York, USA.
  • 16 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
  • 17 1] Institute of Psychology, Chinese Academy of Sciences, Beijing, China. [2] Statistical Genetics, Rockefeller University, New York, New York, USA.
  • 18 Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
  • 19 Centre Hospitalier Universitaire de Caen, Cytogénétique Postnatale et Génétique Clinique, Caen, France.
  • 20 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.
  • 21 Department of Neurosurgery, Bundeswehrkrankenhaus Ulm, Ulm, Germany.
  • 22 Department of Pediatrics, Griffith Base Hospital, Griffith, New South Wales, Australia.
  • 23 Department of Ophthalmology, Hospital Ludwigshafen, Ludwigshafen, Germany.
  • 24 HealthTwist, Berlin, Germany.
  • 25 Institute for Medical Genetics, University of Zurich, Zurich, Switzerland.
  • 26 1] Cardiology Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA. [2] Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA. [3] Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.
  • 27 1] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [2] DZHK (German Centre for Cardiovascular Research), Berlin, Germany. [3] Charité Universitätsmedizin, Berlin, Germany.
  • 28 Department of Nephrology, Hannover University Medical School, Hannover, Germany.
  • 29 Department of Pediatric Oncology, Hacettepe University, Ankara, Turkey.
  • 30 1] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [2] DZHK (German Centre for Cardiovascular Research), Berlin, Germany.
  • 31 Department of Pediatric Cardiology, Children's Hospital, Friedrich Alexander University Erlangen, Erlangen, Germany.
PMID: 25961942 DOI: 10.1038/ng.3302
Abstract

Cardiovascular Disease is the most common cause of death worldwide, and hypertension is the major risk factor. 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). 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 untreated. 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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