The plasma protein factor XII (FXII, F12 or Hageman factor) is a serine protease that is mainly produced in the liver and circulates in plasma (40 μg/mL) as a single chain zymogen. Following contact with anionic surfaces such as extracellular RNA, endotoxin, neutrophil extracellular traps (NETs), polyphosphates released from activated platelets, collagen exposed on injured endothelium, heparin secreted from mast cells, and phosphatidylserine on apoptotic cells, FXII undergoes autoactivation to FXIIa (F12a) via proteolysis of the peptide bond R372-V373 in FXII zymogen (Renné T et al. 2012; Müller F et al. 2009; Oschatz C et al. 2011; Ivanov I et al. 2017; Mailer RKW et al. 2019). Active protease FXIIa is composed of a heavy (20-372) chain and a light (373-615) chain. The light chain harbors the enzymatic protease domain and is linked to the heavy chain by a single disulfide bridge. FXIIa then cleaves plasma prekallikrein to kallikrein, which in turn reciprocally activates additional molecules of FXII and amplifies FXIIa generation (Renné T et al. 2012). Kallikrein also cleaves high-molecular-weight kininogen (HK), releasing the vasoactive peptide bradykinin (BK) (Renné T et al. 2012). BK binds to kinin receptors (B2 and B1 receptors) and triggers inflammation (Leeb-Lundberg LM et al. 2005). The contact system is controlled mainly by C1 inhibitor (C1-Inh or SERPING1) that inhibits both FXIIa and kallikrein.

Hereditary angioedema (HAE) is a rare life-threatening inherited edema disorder that is characterized by recurrent episodes of acute swelling involving the skin or the oropharyngeal, laryngeal, or gastrointestinal mucosa (Zuraw BL & Christiansen SC 2016; de Maat S et al. 2018; Magerl M et al. 2017). Increased vascular permeability in HAE is due to excessive formation of the proinflammatory peptide hormone bradykinin (BK) (Joseph K et al. 2008). Elevated plasma levels of BK are consistently found during acute swelling attacks in HAE patients (Schapira M et al. 1983; Cugno M et al. 2003). Angioedema initiated by bradykinin is usually associated with SERPING1 (С1-Inh) deficiency (HAE type I and HAE type II) (Kaplan AP & Joseph K 2014, 2016; Levi M et al. 2018). More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Magerl M et al. 2017; Zuraw BL 2018; Ivanov I et al. 2019). Using genome-wide linkage analyses, HAE type III was shown to be associated with single missense mutations (c.1032C>A or c.1032C>G) in the F12 gene (Dewald G & Bork K 2006; Cichon S et al. 2006). Both point mutations translate into amino acid substitution of threonine 328 by either a lysine or an arginine residue (T328K or T328R). FXII-linked HAE is an autosomal dominant inherited disorder, and a mixture of wild type and T328-mutated FXII circulates in plasma of patients with HAE type III (Cichon S et al. 2006). An FXII-neutralizing antibody attenuated pathological BK formation in the plasma of patients with HAE type III and blunted edema in a genetically altered, humanized mouse model of HAE type III (Björkqvist J et al. 2015). Moreover, FXII T328K or T328R variants change protein O-linked glycosylation and introduce a new site that is sensitive to enzymatic cleavage by fibrinolytic and coagulation proteases such as plasmin, thrombin or FXIa (Björkqvist J et al. 2015; de Maat S et al. 2016; Ivanov I et al. 2019). FXII T328K or T328R variants are cleaved after residue 328 by proteases, removing the protein’s noncatalytic heavy chain (HC) region. Further, truncation of the pathological FXII T328K by plasmin was found to expose R372 for subsequent cleavage by plasma kallikrein in solution (de Maat S et al. 2016, 2019). The intrinsic capacity of the truncated form of FXII (329-615) variant to convert PK to kallikrein is greater than that of activated FXIIa leading to more kallikrein generated early during reciprocal activation (Ivanov I et al. 2019). Second, the truncated form of FXII (329-615) is a better kallikrein substrate than is FXII (Ivanov I et al. 2019). SERPING1 (C1-Inh), the major inhibitor of FXIIa, binds similarly to wild type (WT) and mutated FXIIa (Björkqvist J et al. 2015). However, the accelerated kallikrein/FXII activation in HAE patients carrying FXII variants appears to overwhelm the regulatory function of SERPING1 at normal plasma levels leading to uncontrolled bradykinin formation in a surface-independent manner (de Maat S et al. 2016; Ivanov I et al. 2019).

The Reactome event describes a truncation of FXII variants after the residue 328 catalyzed by activated thrombin.