A tiny change to a single gene has significant impact on the lives of people in a small village in Turkey. Some pass on the rare disease known as Bilginturan syndrome to their children. Those who are affected have noticeably short fingers, which pose no particular problem for their health, but another, invisible aspect of their condition does. Their blood pressure reaches astronomical heights, and without treatment, those with the syndrome usually suffer fatal strokes before the age of 50.
A research saga going back more than 20 years
For more than 20 years, Fred Luft's research group in Buch has been investigating the syndrome, and the current study is a collaboration with two former members of the team: Okan Toka of Erlangen University and Jens Tank of Hannover Medical School. Luft's group is a part of the Experimental and Clinical Research Center, a collaborative venture of the MDC and the Charité Berlin. Recently the scientists traced the cause of the disorder to a mutation in a gene that encodes an enzyme called phosphodiesterase 3A (PDE3A). PDE3A both regulates blood pressure and influences bone growth – leading to a coupling of hypertension with short fingers. The rare mutation has also been found in families in Canada, the U.S., France and South Africa. The scientific saga has been the subject of an entire popular science book and a report in the German magazine Stern.
Surprisingly, the mutation doesn’t cause organ damage
Most patients' problems with high blood pressure are a product of lifestyle factors rather than mutations, although variations in genes may play a role. The rise in pressure often triggers an enlargement of the heart, problems with the retinal vessels in the eye and kidney damage. But recent studies showed that patients with the PDE3A mutation rarely experience such organ damage. In the current study, just out in the journal Hypertension, the scientists studied the functions of the heart and blood vessels and their interactions (ventricular-arterial coupling). They also examined blood platelets, which are responsible for blood clotting, because these cells contain large quantities of the PDE3A enzyme. The scientists found no significant differences between the organs or platelets of the four people with Bilginturan syndrome and those of four individuals in a control group.
Why the PDE3A mutation is harmful
The mutated form of the PDE3A enzyme is more active than healthy variants of the molecule, which means that it is more efficient at processing its target molecule: the messenger molecule “cyclic adenosine monophosphate” (cAMP). Cells with the mutation break down cAMP at a faster rate and this makes levels of the molecule drop quickly. Lower amounts of cAMP probably allow the smooth muscle surrounding the blood vessels to contract, which would narrow the vessels although the same amount of blood is passing through – raising the pressure. At the same time, PDE3A triggers a faster growth of smooth muscle, creating a thicker sheath around the blood vessels. When this goes on for years, the body loses its ability to detect changes in blood pressure and respond by regulating it in an appropriate way. Pressure rises until it is too high for arteries in the brain and they rupture, resulting in a stroke.
New ways of treating high blood pressure
This situation suggests that reducing the activity of PDE3A might prevent cAMP levels from falling – potentially a promising new avenue for treatments. The scientists found that “cyclic guanosine monophosphate” (cGMP), a molecule closely related to cAMP, lowers the activity of PDE3A in cell cultures. This inhibits levels of cAMP and would presumably relax blood vessels in the body.
Unfortunately, cGMP can't simply be turned into a drug because it is naturally produced in the body and has wide variety of tasks. It isn't affected by blood pressure drugs like Milrinone and Cilostazol – which work by inhibiting the activity of PDE3A, but these drugs have strong side effects. So they are not an option for treating patients with Bilginturan syndrome over the long term.
A better strategy, perhaps, would be to increase the amount of cGMP in cells by stimulating the enzymes that produce it, for example the molecule soluble guanylyl cyclase. More cGMP would lower the activity of PDE3A and thus lead, indirectly, to higher levels of cAMP. In the best case, it would counteract the constriction of blood vessels and thus reduce blood pressure.
Guanylyl cyclase-stimulating substances already exist and are currently being tested in clinical trials. Turning them into safe and effective drugs will take time. But finally, after many decades of research, there is hope for a group of people in a small Turkish village and others around the globe who are affected by Bilginturan syndrome.
Okan Toka, Jens Tank, Carolin Schächterle, Atakan Aydin, Philipp G. Maass, Saban Elitok, Eireen Bartels-Klein, Irene Hollfinger, Carsten Lindschau, Knut Mai, Michael Boschmann, Gabriele Rahn, Matthew A. Movsesian, Thomas Müller, Andrea Doescher, Simone Gnoth, Astrid Mühl, Hakan R. Toka, Yvette Wefeld-Neuenfeld, Wolfgang Utz, Agnieszka Töpper, Jens Jordan, Jeanette Schulz-Menger, Enno Klussmann, Sylvia Bähring, Friedrich C. Luft., Hypertension 66, 800-808. doi:10.1161/HYPERTENSIONAHA.115.06000