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  PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Maass, P. G., Aydin, A., Luft, F. C., Schachterle, C., Weise, A., Stricker, S., et al. (2015). PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nature Genetics, 47(6), 647-653. doi:10.1038/ng.3302.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-60CF-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-60D0-E
Genre: Journal Article

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© 2015 Macmillan Publishers Limited
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 Creators:
Maass, P. G., Author
Aydin, A., Author
Luft, F. C., Author
Schachterle, C., Author
Weise, A., Author
Stricker, S.1, 2, Author              
Lindschau, C., Author
Vaegler, M., Author
Qadri, F., Author
Toka, H. R., Author
Schulz, H., Author
Krawitz, P. M.1, 3, 4, Author
Parkhomchuk, D., Author
Hecht, J.1, 3, Author              
Hollfinger, I., Author
Wefeld-Neuenfeld, Y., Author
Bartels-Klein, E., Author
Muhl, A., Author
Kann, M., Author
Schuster, H., Author
Chitayat, D., AuthorBialer, M. G., AuthorWienker, T. F.5, Author              Ott, J., AuthorRittscher, K., AuthorLiehr, T., AuthorJordan, J., AuthorPlessis, G., AuthorTank, J., AuthorMai, K., AuthorNaraghi, R., AuthorHodge, R., AuthorHopp, M., AuthorHattenbach, L. O., AuthorBusjahn, A., AuthorRauch, A., AuthorVandeput, F., AuthorGong, M., AuthorRuschendorf, F., AuthorHübner, N., AuthorHaller, H., AuthorMundlos, S.1, 3, 4, Author              Bilginturan, N., AuthorMovsesian, M. A., AuthorKlussmann, E., AuthorToka, O., AuthorBahring, S., Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany, ou_persistent22              
3Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
4Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
5Clinical Genetics (Thomas F. Wienker), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, 1479643              

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Free keywords: Adolescent Adult Amino Acid Sequence Animals Base Sequence Brachydactyly/*genetics Case-Control Studies Cell Differentiation Child Cyclic Nucleotide Phosphodiesterases, Type 3/*genetics Female Genetic Association Studies HeLa Cells Humans Hypertension/*congenital/genetics Kinetics Male Mesenchymal Stromal Cells/physiology Mice Middle Aged Molecular Sequence Data Mutation, Missense Myocytes, Smooth Muscle/physiology Pedigree
 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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Language(s): eng - English
 Dates: 2015-05-112015-06
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/ng.3302
ISSN: 1546-1718 (Electronic)1061-4036 (Print)
 Degree: -

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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 47 (6) Sequence Number: - Start / End Page: 647 - 653 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609