Joint Transnational Call 2007 (JTC2007)


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.

  • Cichon, Sven (Coordinator)
    University of Bonn, Life & Brain Center Department of Genomics [GERMANY]
  • Drouet, Christian
    University Joseph Fourier Grenoble National Center for Angioedema [FRANCE]
  • Hennies, Hans Christian
    Cologne Center for Genomic Division of Dermatogenetics [GERMANY]
  • Colombo, Roberto
    IRCCS Don Carlos Gnocchi Foundation Laboratory of Molecular Medicine and Biotechnologies [ITALY]
  • Renné, Thomas
    University Hospital Würzburg Institue for Clinical Biochemistry and Pathobiochemistry [GERMANY]
  • Yapici, Zuhal
    Instanbul Faculty of Medicine Department of Neurology [TURKEY]