Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema

Background Recent studies reported a gain-of-function mutation in the gene encoding coagulation Factor XII (F12) among 5 German and French families with estrogen-associated angioedema who share a common ancestor. The role of this factor, additional pathways that might contribute to increased bradykinin levels, or both remain to be determined in other families with estrogen-dependent or estrogen-associated inherited angioedema. Objective The purpose of this study was to determine whether mutations in F12 and polymorphisms in the genes encoding aminopeptidase P (APP) and angiotensin I–converting enzyme (ACE), which have been associated with increased bradykinin levels, contribute to estrogen-dependent inherited angioedema in a large family of Italian origin. Methods We screened the coding regions of F12 and the gene encoding membrane-bound APP ( XPNPEP2 ), for genetic variants in the 3 affected female subjects. In addition, we genotyped this family for the insertion/deletion polymorphism in the ACE gene, which accounts for variable ACE levels. Results The 3 affected female subjects all have the threonine-to-lysine (Thre328Lys) mutation, which is associated with higher Factor XII activity. In addition, they have at least one A allele of rs3788853 at the XPNPEP2 locus, which is associated with lower APP activity, and at least one I allele in ACE , which is associated with reduced ACE activity. Conclusion A missense mutation in F12 is present in the 3 affected female subjects of this family with estrogen-dependent inherited angioedema. In addition, these affected females have polymorphisms associated with lower levels of both APP and ACE, the major enzymes responsible for bradykinin degradation. Thus, our study suggests that multiple genes might contribute to estrogen-dependent or estrogen-associated inherited angioedema and explain some of the observed heterogeneity.