PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Maass PG, Aydin A, Luft FC, Schaechterle C, Weise A, Stricker S, Lindschau C, Vaegler M, Qadri F, Toka HR, Schulz H, Krawitz PM, Parkhomchuk D, Hecht J, Hollfinger I, Wefeld-Neuenfeld Y, Bartels-Klein E, Muehl A, Kann M, Schuster H, Chitayat D, Bialer MG, Wienker TF, Ott J, Rittscher K, Liehr T, Jordan J, Plessis G, Tank J, Mai K, Naraghi R, Hodge R, Hopp M, Hattenbach LO, Busjahn A, Rauch A, Vandeput F, Gong M, Rueschendorf F, Huebner N, Haller H, Mundlos S, Bilginturan N, Movsesian MA, Klussmann E, Toka O, Baehring S (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 47

Pages Range: 647-53

Journal Issue: 6

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.

Involved external institutions

Northwell Health United States (USA) (US) University of Toronto Canada (CA) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) George E. Wahlen Department of Veterans Affairs Medical Center United States (USA) (US) Hacettepe University Turkey (TR) Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics Germany (DE) Gottfried Wilhelm Leibniz Universität Hannover Germany (DE) University of Zurich / Universität Zürich (UZH) Switzerland (CH) HealthTwiSt GmbH Germany (DE) Klinikum der Stadt Ludwigshafen am Rhein gGmbH Germany (DE) Griffith Base Hospital Australia (AU) Bundeswehrkrankenhaus Ulm Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Centre Hospitalier Universitaire de Caen France (FR) Friedrich-Schiller-Universität Jena Germany (DE) Chinese Academy of Sciences (CAS) / 中国科学院 China (CN) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universität zu Köln Germany (DE)

How to cite

APA:

Maass, P.G., Aydin, A., Luft, F.C., Schaechterle, C., Weise, A., Stricker, S.,... Baehring, S. (2015). PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nature Genetics, 47(6), 647-53. https://doi.org/10.1038/ng.3302

MLA:

Maass, Philipp G., et al. "PDE3A mutations cause autosomal dominant hypertension with brachydactyly." Nature Genetics 47.6 (2015): 647-53.

BibTeX: Download