title: PDE3A mutations cause autosomal dominant hypertension with brachydactyly.
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.
authors.affiliation: 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.
authors.forename: Philipp G
authors.initials: PG
authors.lastname: Maass
authors.affiliation: 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.
authors.forename: Atakan
authors.initials: A
authors.lastname: Aydin
authors.affiliation: 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.
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schächterle
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Weise
authors.affiliation: 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.affiliation: 1] Department of Nephrology, Hannover University Medical School, Hannover, Germany. [2] Staatliche Technikerschule Berlin, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Lindschau
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Vaegler
authors.affiliation: 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.
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.affiliation: 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.
authors.forename: Hakan R
authors.initials: HR
authors.lastname: Toka
authors.affiliation: 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.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.affiliation: 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.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Krawitz
authors.affiliation: 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.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Parkhomchuk
authors.affiliation: 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Hollfinger
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Wefeld-Neuenfeld
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Eireen
authors.initials: E
authors.lastname: Bartels-Klein
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Mühl
authors.affiliation: 1] Department II of Medicine, University of Cologne, Cologne, Germany. [2] Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kann
authors.affiliation: INFOGEN, Berlin, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schuster
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: 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.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Bialer
authors.affiliation: 1] Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.affiliation: 1] Institute of Psychology, Chinese Academy of Sciences, Beijing, China. [2] Statistical Genetics, Rockefeller University, New York, New York, USA.
authors.forename: Jürg
authors.initials: J
authors.lastname: Ott
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rittscher
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.affiliation: Centre Hospitalier Universitaire de Caen, Cytogénétique Postnatale et Génétique Clinique, Caen, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Plessis
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Tank
authors.affiliation: 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.
authors.forename: Knut
authors.initials: K
authors.lastname: Mai
authors.affiliation: Department of Neurosurgery, Bundeswehrkrankenhaus Ulm, Ulm, Germany.
authors.forename: Ramin
authors.initials: R
authors.lastname: Naraghi
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Russell
authors.initials: R
authors.lastname: Hodge
authors.affiliation: Department of Pediatrics, Griffith Base Hospital, Griffith, New South Wales, Australia.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Hopp
authors.affiliation: Department of Ophthalmology, Hospital Ludwigshafen, Ludwigshafen, Germany.
authors.forename: Lars O
authors.initials: LO
authors.lastname: Hattenbach
authors.affiliation: HealthTwist, Berlin, Germany.
authors.forename: Andreas
authors.identifier: 0000000196506919
authors.initials: A
authors.lastname: Busjahn
authors.affiliation: Institute for Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: 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.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Vandeput
authors.affiliation: 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.
authors.forename: Maolian
authors.initials: M
authors.lastname: Gong
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.affiliation: 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.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: Department of Nephrology, Hannover University Medical School, Hannover, Germany.
authors.forename: Hermann
authors.initials: H
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authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Department of Pediatric Oncology, Hacettepe University, Ankara, Turkey.
authors.forename: Nihat
authors.initials: N
authors.lastname: Bilginturan
authors.affiliation: 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.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Movsesian
authors.affiliation: 1] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [2] DZHK (German Centre for Cardiovascular Research), Berlin, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
authors.affiliation: Department of Pediatric Cardiology, Children's Hospital, Friedrich Alexander University Erlangen, Erlangen, Germany.
authors.forename: Okan
authors.initials: O
authors.lastname: Toka
authors.affiliation: 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.
authors.forename: Sylvia
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mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D059327:Brachydactyly / Q000235:genetics*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002648:Child; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006367:HeLa Cells; D006801:Humans; D006973:Hypertension / Q000151:congenital* / Q000235:genetics; D007700:Kinetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D010375:Pedigree
chemical_list: D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human