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PDE3A mutations cause autosomal dominant hypertension with brachydactyly
Maass, Philipp G.1,2; Aydin, Atakan1,2; Luft, Friedrich C.1,2,3; Schaechterle, Carolin2; Weise, Anja4; Stricker, Sigmar5,6; Lindschau, Carsten7,8; Vaegler, Martin1,2,9; Qadri, Fatimunnisa1,2; Toka, Hakan R.1,10,11; Schulz, Herbert2,12; Krawitz, Peter M.5,13,14; Parkhomchuk, Dmitri13,14; Hecht, Jochen14; Hollfinger, Irene2; Wefeld-Neuenfeld, Yvette2; Bartels-Klein, Eireen2; Muehl, Astrid2; Kann, Martin15,16; Schuster, Herbert17; Chitayat, David18,19; Bialer, Martin G.20,21; Wienker, Thomas F.22; Ott, Juerg23,24; Rittscher, Katharina4; Liehr, Thomas4; Jordan, Jens25; Plessis, Ghislaine26; Tank, Jens25; Mai, Knut1,2; Naraghi, Ramin27; Hodge, Russell; Hopp, Maxwell28; Hattenbach, Lars O.29; Busjahn, Andreas30; Rauch, Anita31; Vandeput, Fabrice32,33,34; Gong, Maolian1,2; Rueschendorf, Franz; Huebner, Norbert2,36; Haller, Hermann7; Mundlos, Stefan5,13,14; Bilginturan, Nihat37; Movsesian, Matthew A.32,33,34; Klussmann, Enno2,35; Toka, Okan38; Baehring, Sylvia1,2
Source PublicationNATURE GENETICS
AbstractCardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor(1). 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 untreated(3,4). 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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WOS IDWOS:000355386500017
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Document Type期刊论文
Affiliation1.Joint Cooperat Charite Med Fac, ECRC, Berlin, Germany
2.Helmholtz Assoc MDC, Max Delbruck Ctr Mol Med, Berlin, Germany
3.Vanderbilt Univ, Sch Med, Dept Med, Div Clin Pharmacol, Nashville, TN 37212 USA
4.Univ Jena, Jena Univ Hosp, Inst Human Genet, Jena, Germany
5.Max Planck Inst Mol Genet, D-14195 Berlin, Germany
6.Free Univ Berlin, Inst Chem & Biochem, Berlin, Germany
7.Leibniz Univ Hannover, Sch Med, Dept Nephrol, D-30167 Hannover, Germany
8.Staatl Technikerschule Berlin, Berlin, Germany
9.Univ Tubingen, Dept Urol, Lab Tissue Engn, Tubingen, Germany
10.Eastern Virginia Med Sch, Div Nephrol & Hypertens, Norfolk, VA 23501 USA
11.Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA
12.Univ Cologne, CCG, D-50931 Cologne, Germany
13.Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany
14.Charite, Berlin Brandenburg Ctr Regenerat Therapies BCRT, D-13353 Berlin, Germany
15.Univ Cologne, Dept Med 2, D-50931 Cologne, Germany
16.Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany
17.INFOGEN, Berlin, Germany
18.Univ Toronto, Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada
19.Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1X5, Canada
20.North Shore LIJ Hlth Syst, Div Med Genet, Manhasset, NY USA
21.North Shore LIJ Hlth Syst, Dept Pediat, Manhasset, NY USA
22.Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany
23.Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China
24.Rockefeller Univ, Stat Genet, New York, NY 10021 USA
25.Hannover Med Sch, Inst Clin Pharmacol, Hannover, Germany
26.CHU Caen, Cytogenet Postnatale & Genet Clin, F-14000 Caen, France
27.Bundeswehrkrankenhaus Ulm, Dept Neurosurg, Ulm, Germany
28.Griffith Base Hosp, Dept Pediat, Griffith, NSW, Australia
29.Hosp Ludwigshafen, Dept Ophthalmol, Ludwigshafen, Germany
30.HealthTwist, Berlin, Germany
31.Univ Zurich, Inst Med Genet, Zurich, Switzerland
32.Vet Affairs Salt Lake City Hlth Care Syst, Cardiol Sect, Salt Lake City, UT USA
33.Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA
34.Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA
35.DZHK German Ctr Cardiovasc Res, Berlin, Germany
36.Charite, D-13353 Berlin, Germany
37.Hacettepe Univ, Dept Pediat Oncol, Ankara, Turkey
38.Univ Erlangen Nurnberg, Childrens Hosp, Dept Pediat Cardiol, D-91054 Erlangen, Germany
Recommended Citation
GB/T 7714
Maass, Philipp G.,Aydin, Atakan,Luft, Friedrich C.,et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly[J]. NATURE GENETICS,2015,47(6):647-653.
APA Maass, Philipp G..,Aydin, Atakan.,Luft, Friedrich C..,Schaechterle, Carolin.,Weise, Anja.,...&Baehring, Sylvia.(2015).PDE3A mutations cause autosomal dominant hypertension with brachydactyly.NATURE GENETICS,47(6),647-653.
MLA Maass, Philipp G.,et al."PDE3A mutations cause autosomal dominant hypertension with brachydactyly".NATURE GENETICS 47.6(2015):647-653.
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