Starting with a severely affected family, a research research team led by Jeanette Erdmann, Christian Hengstenberg and Heribert Schunkert (Institut für Integrative und Experimentelle Genomik, University of Lübeck and Deutsches Herzzentrum München) identified a novel mechanism leading to myocardial infarction. Specifically, the scientists detected two mutations that jointly blocked nitric oxide signalling in platelets leading to accelerated thrombus formation.
Another variant of the same enzyme, affecting a large proportion of the population, was also found to affect coronary risk, albeit to a much lesser extend. The project was funded by the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.). The work was published on November 10th in the prestigious journal Nature.
Coronary artery disease and its sequelae myocardial infarction are among the leading causes of death worldwide. In addition to an unhealthy lifestyle, it is known for a long time that familial or inherited factors contribute to the development of these diseases. Now, an international team of 42 researchers from 36 institutions and 7 countries unravelled a novel cause of myocardial infarction in an extraordinary large German family comprising more than 23 affected family members.
Next-generation sequencing made it feasible to pinpoint disease-causing mutations.
“In our case the surprising finding was that two mutations affecting the same enzyme came together in a family with an extraordinary high myocardial infarction risk“ adds Heribert Schunkert from the Deutsches Herzzentrum Munich. Jeanette Erdmann specifies: „We identified two private mutations in the functionally related genes, GUCY1A3 and CCT7. Extensive follow-up studies revealed that these genes encode proteins that work together to mediate effects following nitric oxide stimulation which, among other actions, inhibit platelet activation“.
“Overall, these data suggest a link between impaired nitric oxide signalling and myocardial infarction risk“ summarizes Christian Hengstenberg from the Deutsches Herzzentrum München. Jeanette Erdmann adds, “Furthermore, we show that it is important not only to search for one disease-causing mutation in families, but to look for two, or even three potentially interacting mutations to explain clustering of a disease in families”.Background
Here, the researchers sequenced, in cooperation with colleagues at the Helmholtz-Zentrum Munich (Tim Strom and Thomas Meitinger), the complete coding regions of the genome (the so-called “exome“) of three affected cousins and looked for mutations shared by these family members and absent in healthy controls. Starting with more than 30.000 of such genetic variants the researches were left in the end with two mutations in GUCY1A3 and CCT7 encoding for proteins that actually interact functionally in an enzyme called soluble guanylyl cyclase (sGC). In fact, if both mutations were found in a family member the effect was a dysfunctional enzyme incapable of responding to nitric oxide stimulation. The effect was by far less if only one of the the mutations were found in a family member.
A subunit of the enzyme soluble guanylyl cyclase (sGC) that is well known to be activated by nitric oxide is encoded by GUCY1A. The second mutation was found in the gene CCT7 which encodes a chaperone protein required for proper folding of newly synthetized cellular proteins. In a cell-based approach, the researchers demonstrated in cooperation with cellular biologists (Frank Kaiser from the Institute of Human Genetics of the University of Lübeck and Doris Koesling from the Institute of Pharmacology and Toxicology of the University of Bochum) that lack of this chaperone protein reduces the cellular amount of sGC resulting in loss of sGC function. Thus, both proteins are required for intact nitric oxide signalling. An important target of nitric oxide signalling are platelets in which aggregation is inhibited by this intercellular messenger. These cells can be easily isolated from the blood and, indeed, were found to be non-responsive to nitric oxide stimulation due to a substantial reduction of sGC protein levels in family members caarying both mutations. Likewise, all family members carrying both mutations developed coronary disease. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
The importance of the nitric oxide signalling pathway on the functional level was verified by a cooperation with Cor de Wit, a physiologist from the Institute of Physiology of the University of Lübeck, who demonstrated accelerated platelet aggregation in mice deficient for this critical subunit of the sGC. The finding in the mice which mimicks the situation in double mutation carriers may provide the mechanistic link between dysfunctional nitric oxide signalling and myocardial infarction since platelet aggregation and thrombus formation may be unopposed in affected individuals rendering them prone for this fatal disease.
Interestingly, genetic data of more than 30.000 MI patients and 80.000 controls pulled together from the international consortium CARDIoGRAM provide evidence that not only very rare mutations in GUCY1A3 lead to MI but also common variants in this gene increases MI risk substantially.Title of publication:
For further information, please contact:Prof. Dr. rer. nat. Jeanette Erdmann
Christine Vollgraf | idw
When fat cells change their colour
28.10.2016 | Albert-Ludwigs-Universität Freiburg im Breisgau
Aquaculture: Clear Water Thanks to Cork
28.10.2016 | Technologie Lizenz-Büro (TLB) der Baden-Württembergischen Hochschulen GmbH
Physicists from the University of Würzburg have designed a light source that emits photon pairs. Two-photon sources are particularly well suited for tap-proof data encryption. The experiment's key ingredients: a semiconductor crystal and some sticky tape.
So-called monolayers are at the heart of the research activities. These "super materials" (as the prestigious science magazine "Nature" puts it) have been...
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
28.10.2016 | Power and Electrical Engineering
28.10.2016 | Physics and Astronomy
28.10.2016 | Life Sciences