Hereditary angioedema (HAE) is due to mutations in C1 inhibitor (C1-INH) gene. C-INH is a serpin that controls activation of complement and contact systems. The clinical phenotype of the disease is highly variable, but the causes of such variability remain undisclosed. Identifying mutations and their molecular effect may identify structure/function as well as genotype/phenotype correlates. 492 HAE patients belonging to 196 unrelated families are regularly followed at our Department and characterized for clinical phenotype. Genotyping of these patients, now in progress, has been completed in 155. Mutations affecting residues primarily involved in the unique suicide substrate-like inhibitory mechanism of serpins have been selected for expression in Pichia pastoris. This expression system provides an average yield of 80mg per liter of culture media with wild type C1-INH. Here we present the results on the function/structure characterization of R378C variant. The patient carrying this mutation presents unusual features compared to other HAE patients: absence of typical subcutaneous angioedema, recurrent short lasting (few hours) abdominal cramps, but no major abdominal symptoms with severe pain vomiting and/or dyarrhea, variable C1-INH plasma levels with spontaneous normalization. The expressed protein has a very low yield, most likely due to an impaired secretory profile, typical of multimerization inside the cells. The inhibitory capacity of the active form is preserved, the second order inhibition constant found in progress curves was comparable to wild-type recombinant C1-INH. This results suggest that the HAE phenotype is due to a failure in general folding and structural stability. The R378C C1-INH variant could undergo different conformations (native, latent, polymer), that result in different degrees of impaired secretion and/or function, depending on specific environmental conditions.
|Titolo:||Structure/function correlates in variables causing hereditary angioedema|
|Autori interni:||CACCIA, SONIA (Primo)|
|Data di pubblicazione:||2006|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Enti collegati al convegno:||Deutsche Forschungsgemeinschaft (DFG)|
|Citazione:||Structure/function correlates in variables causing hereditary angioedema / S. Caccia. ((Intervento presentato al 6. convegno International Workshop on C1, the First Component of Complement, Collectins and Ficolins tenutosi a Mainz nel 2006.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|