Individuals with this altered gene have hereditary hypertension and a skeletal malformation called brachydactyly type E, which is characterized by unusually short fingers and toes. The effect on blood pressure is so serious that – if left untreated – it most often leads to death before age fifty.
After more than 20 years of research, scientists of the Experimental and Clinical Research Center (ECRC), a joint cooperation between the Max Delbrück Center (MDC) and the Charité – Universitätsmedizin Berlin have now identified the gene that causes this rare syndrome (Nature Genetics online doi:10.1038/ng.3302)*.
In six families not related to each other they discovered different point mutations in the gene PDE3A. These mutations always lead to high blood pressure and shortened bones of the extremities, particularly the metacarpal and metatarsal bones. This syndrome is the first Mendelian hypertension (salt-resistant) not based on salt reabsorption but instead is more directly related to resistance in small blood vessels.
“In 1994, when we began with the study of this disease and examined the largest of the affected families in Turkey for the first time, modern DNA sequencing methods did not yet exist. Extensive gene databases to facilitate the search for the cause of this genetic disease were also lacking back then,” said PD Dr. Sylvia Bähring, senior author of the research group’s publication headed by Professor Friedrich C. Luft.
“Veritable treasure trove for genetics”
In 1996, the research group succeeded in comparing the genetic material of healthy and diseased family members in order to localize the chromosome region where this disease gene must reside. The region they detected was on a segment of chromosome 12 and was an estimated 10 million base pairs in size.
“Ultimately however,” said Dr. Bähring, “a 16-year-old Turkish boy helped us to pinpoint this gene. He is a veritable treasure trove for the field of genetics.” He also has severe high blood pressure – like all other test subjects he is being treated anti-hypertensive drugs –- but his hands are nearly normal. Only the metacarpal bones of his little fingers are slightly shortened.
Whole-genome sequencing of the DNA from several people with the syndrome recently enabled Dr. Philipp G. Maass, Dr. Atakan Aydin, Professor Luft, Dr. Okan Toka (formerly MDC/Charité, now the University of Erlangen), Dr. Carolin Schächterle (MDC research group Dr. Enno Klußmann) and Dr. Bähring to identify the gene and six different point mutations in a total of six families from around the world.
It is the gene PDE3A, which contains the blueprint for the enzyme, phosphodiesterase 3A. The six different point mutations, which the researchers pinpointed in the PDE3A gene, lead to the exchange of a single DNA building block that is different in each family. In each case, one amino acid of the enzyme is exchanged.
One gene – two different syndromes
But how can one mutated gene cause two quite different diseases such as hypertension and brachydactyly? The ECRC researchers also provide the explanation for this in their study. The task of the phosphodiesterase encoded by the PDE3A gene is to control the quantity of the two secondary messenger proteins present in each cell, cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate), and thus to regulate the duration of their activity.
The mutations in the gene PDE3A, however, cause the enzyme phosphodiesterase to be overexpressed. Thus, it modulates too much of the secondary messenger protein cAMP (cyclic adenosine monophosphate) into AMP (adenosine monophosphate). As a result, the cell has less cAMP at its disposal.
The consequence is that, in the affected family members, the smooth muscle cells of the vascular wall of small arteries divide to a greater extent. This proliferation leads to a thickening of the vascular muscle layer, and the blood vessels narrow and stiffen, resulting in high blood pressure. Furthermore, a too low cAMP level in the vascular muscle cells also leads to increased narrowing of the blood vessels.
But what effect do the lowered cAMP levels have on the development of the bones of the extremities? The gene that elicits the skeletal malformation brachydactyly type E is PTHLH (parathyroid hormone-like hormone). In the cartilage cells, a transcription factor (CREB), activated by cAMP, binds in the control region of the gene. This factor ensures that the gene is transcribed and can affect the growth of the cartilage. If there is less cAMP in the cartilage cell, this mechanism is disturbed. This situation then leads to the shortening of the metacarpals and metatarsals, namely the fingers and toes. Thus, by varying the cellular signal transduction, one point mutation can elicit two different characteristics in one and the same person.
New perspectives on hypertension development
The researchers point out that hypertension in the families they examined is not linked to dietary salt intake. The consensus of researchers so far has been that too much salt in the diet damages the kidneys and drives blood pressure up. “We have shown in our study that for the development of the inheritable form of hypertension only the blood vessels are of significance and not directly the kidneys,” said Dr. Bähring, stressing the importance of this study.
First description of the disease in 1973
In 1973, the Turkish physician, Professor Nihat Bilginturan, of the Haceteppe University in Ankara, Turkey first described the disease whose genetic cause has now been elucidated by the researchers in Berlin. Dr Bilginturan noted that in an extended family living on the coast of the Black Sea several family members had shortened fingers and toes – the medical term for this syndrome is brachydactyly (from Greek: brachus for short and daktylos for finger).
Remarkably, the affected family members also had severe high blood pressure from youth on and died at a relatively young age. Untreated, their blood pressure exceeded the normal level of 140/90 mm Hg by an average of 50 mm Hg, leading to death before the age of 50, usually due to stroke. The geneticist Professor Thomas Wienker (formerly of the MDC and the University of Bonn, now at the Max Planck Institute for Molecular Genetics, Berlin) discovered Bilginturan’s publication and set the wheels of research in motion.
*PDE3A mutations cause autosomal-dominant hypertension with brachydactyly
Philipp G. Maass1,2,36, Atakan Aydin1,2,36, Friedrich C. Luft1,2,3,36*, Carolin Schächterle2,36,Anja Weise4, Sigmar Stricker5,6, Carsten Lindschau7,8, Martin Vaegler1,9, Fatimunnisa Qadri1,2, Hakan R. Toka10,11, Herbert Schulz2,12, Peter M. Krawitz5,13,14, Jochen Hecht5,14, Irene Hollfinger2, Yvette Wefeld-Neuenfeld2, Eireen Bartels-Klein2, Astrid Mühl2, Martin Kann15, Herbert Schuster16, David Chitayat17,18, Martin G. Bialer19, Thomas F. Wienker5,20, Jürg Ott21,22, Katharina Rittscher4, Thomas Liehr4, Jens Jordan23, Ghislaine Plessis24, Jens Tank23, Knut Mai1, Ramin Naraghi24, Russell Hodge2, Maxwell Hopp26, Lars O. Hattenbach27, Andreas Busjahn28, Anita Rauch29, Fabrice Vandeput30,31, Maolian Gong1,2, Franz Rüschendorf2, Norbert Hübner2,32,33, Hermann Haller7, Stefan Mundlos5,13,14, Nihat Bilginturan34, Matthew A. Movsesian30,31, Enno Klussmann2,32, Okan Toka35, and Sylvia Bähring1,2,36
1Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
2Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
3Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
4Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Jena, Germany
5Max Planck Institute for Molecular Genetics, Berlin, Germany
6Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
7 Department of Nephrology, Hannover University Medical School, Hannover, Germany
8Staatliche Technikerschule Berlin, Berlin
9University Department of Urology, Laboratory of Tissue Engineering, Eberhard Karls University Tübingen, Tübingen, Germany
10 Eastern Virginia Medical School, Division of Nephrology and Hypertension, 855 W Brambleton Ave, Norfolk, VA, USA
11Brigham and Women’s Hospital, Division of Nephrology, MRB4, Boston, MA, USA
12University of Cologne, Cologne Center for Genomics (CCG), Cologne, Germany
13Institute for Medical Genetics and Human Genetics, Charité – Universitätsmedizin Berlin, Germany
14Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Germany
15Department II of Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
16INFOGEN, Berlin, Germany
17The Hospital for Sick Children, Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Ontario, Canada
18The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada
19Division of Medical Genetics and Department of Pediatrics, North Shore/LIJ Health System, Manhasset, NY, USA
20Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany
21Institute of Psychology, Chinese Academy of Sciences, Beijing, China
22Statistical Genetics, Rockefeller University New York, NY, USA
23Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
24Centre Hospitalier Universitaire de Caen, Cytogénétique postnatale et génétique Clinique, Caen, France
25Department of Neurosurgery, Bundeswehrkrankenhaus Ulm, Germany
26Griffith Base Hospital, Department of Pediatrics, Griffith, NSW, Australia
27Department of Ophthalmology, Hospital Ludwigshafen, Ludwigshafen, Germany
28HealthTwist GmbH, Berlin, Germany
29Institute for Medical Genetics, University of Zurich, Switzerland
30Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT, USA
31Departments of Internal Medicine and Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
32DZHK, German Centre for Cardiovascular Research, Berlin, Germany
33Charité – Universitätsmedizin, Berlin, Germany
34Department of Pediatric Endocrinology, Hacettepe University, Turkey
35Childrens Hospital, Department of Pediatric Cardiology, Friedrich-Alexander University Erlangen, Germany
36The authors contributed equally to this work.
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