HAE III

Our proposal concerns a rare, potentially life-threatening swelling disease, named hereditary angioedema type III (HAE type III). In a collaborative effort between research groups from Germany, France, and Italy, we plan to analyze the genetic basis and pathophysiology of HAE type III. In contrast to the well-understood hereditary angioedema types I and II that are due to hereditary deficiency of C1 esterase inhibitor (a plasma protease inhibitor, which targets plasma kallikrein), this inherited disease is described exclusively in women. As a result of a successful collaboration between the research groups that submit the current proposal, we could recently identify the first genetic defect associated with this severe disease, single point mutations in the gene of coagulation factor XII (Hageman factor, Cichon et al., Am J. Hum Genetics, 2006). Clotting factor XII initiates the intrinsic pathway of coagulation and triggers formation of the inflammatory mediator bradykinin.
Strikingly, our research results clearly indicate that only a relatively small fraction of hereditary angioedema type III cases can be attributed to coagulation factor XII. It is evident that other, so far unknown genes, must play a role in disease development. Identification of these genes is one goal of the proposed project. Combining the family and patient samples collected by the participating groups, we have very high chances to successfully identify such genes.
 
In parallel to these genetic analyses, we will focus on characterizing the pathomechanism of the factor XII-associated hereditary angioedema type III using edema-formation models in genetically altered mice. These studies will provide an in-depth understanding of the molecular causes for angioedema type III. This project offers the unique chance to identify new targets to fight hereditary angioedema and to develop convenient tools for predictive testing of the disease. It may also open new avenues for edema therapy in other disease states such as diabetic retinopathy, asthmatic disease or inflammation. We believe that our project proposal fits very well with the goals envisaged by the E-RARE programme.