Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Genetics, Pathophysiology, and Therapy of Hereditary Angioedema Type III

Project Coordinator

University of Bonn, Life & Brain Center Department of Genomics


Christian Drouet University Joseph Fourier Grenoble National Centre for Angioedema Grenoble, France
Hans Christian Hennies Cologne Center for Genomic Division of Dermatogenetics Köln, Germany
Konrad Bork University of Mainz Department of Dermatology Mainz, Germany
Roberto Colombo IRCCS Don Carlo Gnocchi Foundation Laboatory of Molecular Medicine and Biotechnologies Milano, Italy
Thomas Renné University Hospital Würzburg Institute for Clinical Biochemistry and Pathobiochemistry Würtzburg, Germany
Zuhal Yapici Istanbul Faculty of Medicine Department of Neurology Istanbul, Turkey

Publications of the HAEIII project

Major results of the project

Hereditary angioedemas (HAE) are clinically characterized by recurrent swelling attacks of the skin, gastrointestinal mucosa and upper respiratory tract. Attacks are potentially lifethreatening, especially when the upper respiratory tract is affected. Two forms of hereditary angioedema, HAE type I and II, have long been known. These forms are caused by mutations in the gene for the enzyme C1 esterase inhibitor (C1INH) which plays a key role in regulating the production of the hormone bradykinin. Bradykinin is involved in mediating the cellular processes leading to the swelling reactions. Recently, a new subtype, HAE type III, was described. In this subtpye, no mutations in C1INH are found. Members of this consortium identified that mutations in the blood coagulation factor XII (FXII) are responsible for a portion of HAE type III patients. Apart from this, not much was known about this new subtype of HAE at the start of this project. Our project therefore aimed at investigating the effects at the molecular level in HAE type III patients with a FXII mutation. Understanding of these pathophysiological molecular processes is an important step towards developing rational therapies which is particularly important given the imminent danger for the patients to die from asphyxation. Further, we aimed to identify so far unknown gene defects causing HAE type III, explain the pathophysiology of these gene defects and use them for diagnostic and therapeutic considerations.

Our network allowed us to assemble the largest database / biobank of HAE type III patients included in research efforts so far, at this point 280 patients/families. This is extremely valuable given the low population frequency of the disease and it will also be of great help for future research efforts. Careful examination of the presence of the known FXII mutation in these patients revealed that only 18% of patients with a clinical diagnosis of HAE type III are caused by FXII mutations. That means that for the majority of the patients, other genetic defects are responsible. Systematic search for these genetic factors resulted in evidence for a possible new mutation in one family, this is currently being followed-up. In other families with HAE type III, we are currently searching for mutations using new DNA-sequencing technologies.
The consortium investigated in detail the molecular processes that result from the disease causing mutation in FXII. A new ELISA assay developed by the consortium will allow straightforward screenings of large patient cohorts with HAE type III for the presence of the known FXII mutations. We now have a better understanding that there is an excessbradykinin formation which leads to the swellings. Mouse models allow for the testing of existing FXII inhibitors and bradykinin receptor antagonists for their impact as medical treatment for HAE type III patients. Although our results obtained so far are still in the range of basic research, our project has established all steps to diagnose and to treat the disease in an early stage. As soon as further mutations and thus pathways involved in the development of HAE type III are identified, these will be characterized functionally which is a prerequisite for pharmacological interventions.
The project has emphasized how important a network strategy with a clear distribution of tasks among the consortium members is. Building on our experience as a E-RARE consortium we are now in the state to extend the results of this project and come to new classifications and pharmacological strategies in HAE with a close interaction of all network partners.

E-Rare 2012 - Created by Toussaint Biger