Plasma Kallikrein Role in Hereditary Angioedema: Genetics and Functional Analysis.

Abstract

The hereditary angioedema (HAE) is characterized by repetitive episodes of painfuledemas and discomfort which affects mainly the upper and lower extremities, gastrointestinaltract, genitals and face, and it can lead to death by asphyxiation in swelling of upperrespiratory tract. The HAE is an autosomal-dominant disorder resulting from mutations in theC1 inhibitor that result in its abnormal levels or functionality (HAE Type I and II,respectively) or the result of other disorders (HAE Type 3) leading to an overproduction ofbradykinin (BK), the peptide responsible for edema. C1-INH is the main physiologic inhibitorof the contact system factor XII (FXII) and plasma kallikrein (huPK), which is responsible forBK release.The aim of this project is to study huPK role in HAE, analyzing its genetic andfunctional alterations in HAE patients, correlating with different patient's symptoms.Thus, genomic DNA will be extracted from peripheral blood cells of HAE patients andPCR will be performed with the flanking regions of all exons and RNA followed bysequencing. Other deletions and duplications will be analyzed by a MLPA-like technique.Protein structure and activity will be analyzed by immunoblotting and enzyme kinetics. Theresults of this project intend to clarify unknown mechanisms involving huPK activity in HAE,and can contribute to better understanding of this huPK role in other physiopathologysituations.